Immunotherapy against melanoma and other cancers

Abstract

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

Claims

1. A peptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 237, and variant sequences thereof which are at least 88% homologous to SEQ ID No. 1 to SEQ ID No. 237, and wherein said variant binds to molecule(s) of the major histocompatibility complex (MHC) and/or induces T cells cross-reacting with said variant peptide; and a pharmaceutical acceptable salt thereof, wherein said peptide is not a full-length polypeptide.

2. The peptide or variant according to claim 1, wherein said peptide or variant has the ability to bind to an MHC class-I or -II molecule, and wherein said peptide, when bound to said MHC, is capable of being recognized by CD4 and/or CD8 T cells.

3. The peptide or variant thereof according to claim 1, wherein the amino acid sequence thereof comprises a continuous stretch of amino acids according to any one of SEQ ID No. 1 to SEQ ID No. 237.

4. The peptide or variant thereof according to claim 1, wherein said peptide or variant thereof has an overall length of from 8 to 100, optionally from 8 to 30, and more preferred from 8 to 16 amino acids, and most preferred wherein the peptide consists or consists essentially of an amino acid sequence according to any of SEQ ID No. 1 to SEQ ID No. 237.

5. A peptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 237, and variant sequences thereof which are at least 88% homologous to SEQ ID No. 1 to SEQ ID No. 237, and wherein said variant binds to molecule(s) of the major histocompatibility complex (MHC) and/or induces T cells cross-reacting with said variant peptide; and a pharmaceutical acceptable salt thereof, wherein said peptide is not a full-length polypeptide, wherein said peptide or variant is modified and/or includes non-peptide bonds.

6. The peptide or variant thereof according to claim 1, wherein said peptide is part of a fusion protein, optionally comprising N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii).

7. An antibody, optionally a soluble or membrane-bound antibody, optionally a monoclonal antibody or fragment thereof, that specifically recognizes the peptide or variant thereof according to claim 1, optionally the peptide or variant thereof that is bound to an MHC molecule.

8. A T-cell receptor, optionally soluble or membrane-bound, or a fragment thereof, that is reactive with an HLA ligand, wherein said ligand is the peptide or variant thereof according to claim 1, optionally the peptide or variant thereof that is bound to an MHC molecule.

9. The T-cell receptor according to claim 8, wherein said ligand amino acid sequence is at least 88% identical to any one of SEQ ID No. 1 to SEQ ID No. 237, or wherein said ligand amino acid sequence consists of any one of SEQ ID No. 1 to SEQ ID No. 237.

10. The T-cell receptor according to claim 8, wherein said T-cell receptor is provided as a soluble molecule and optionally carries a further effector function optionally an immune stimulating domain or toxin.

11. An aptamer that specifically recognizes the peptide or variant thereof according to claim 1, optionally the peptide or variant thereof that is bound to an MHC molecule.

12. A nucleic acid, encoding for a peptide or variant thereof according to claim 1, an antibody or fragment thereof, a T-cell receptor or fragment thereof, optionally linked to a heterologous promoter sequence, or an expression vector expressing said nucleic acid.

13. A recombinant host cell comprising the peptide or variant according to claim 1, an antibody or fragment thereof, a T-cell receptor or fragment thereof, or a nucleic acid or expression vector thereof, wherein said host cell optionally is selected from an antigen presenting cell, optionally a dendritic cell, a T cell or an NK cell.

14. An in vitro method for producing activated T lymphocytes, the method comprising contacting in vitro T cells with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said T cells in an antigen specific manner, wherein said antigen is a peptide or variant according to claim 1.

15. An activated T lymphocyte, produced by the method according to claim 14, that selectively recognizes a cell which presents a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 237, and variant sequences thereof which are at least 88% homologous to SEQ ID No. 1 to SEQ ID No. 237.

16. A pharmaceutical composition comprising at least one active ingredient selected from the group consisting of the peptide or variant according to claim 1, an antibody or fragment thereof, a T-cell receptor or fragment thereof, an aptamer thereof, a nucleic acid or the expression vector thereof, a host cell thereof, or an activated T lymphocyte thereof, or a conjugated or labelled active ingredient, and a pharmaceutically acceptable carrier, and optionally, one or more pharmaceutically acceptable excipients and/or stabilizers.

17. A method for producing the peptide or variant thereof according to claim 1, an antibody or fragment thereof or a T-cell receptor or fragment thereof, the method comprising culturing a host cell, and isolating the peptide or variant thereof, the antibody or fragment thereof or the T cell receptor or fragment thereof from said host cell and/or its culture medium.

18. The peptide or variant according to claim 1, an antibody or fragment thereof, a T-cell receptor or fragment thereof, an aptamer thereof, a nucleic acid or expression vector thereof, a host cell thereof, or an activated T lymphocyte thereof, for use in medicine.

19. A method for killing target cells in a patient which target cells present a peptide or variant of claim 1, the method comprising administering to the patient an effective number of activated T cells that selectively recognize a cell which presents a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 237, and variant sequences thereof which are at least 88% homologous to SEQ ID No. 1 to SEQ ID No. 237.

20. A product comprising a peptide or variant according to claim 1, an antibody or fragment thereof, a T-cell receptor or fragment thereof, an aptamer thereof, a nucleic acid or expression vector thereof, a host cell thereof, or an activated T lymphocyte thereof, for use in diagnosis and/or treatment of cancer, or for use in the manufacture of a medicament against cancer.

21. The product according to claim 20, wherein said cancer is selected from the group of melanoma, acute myelogenous leukemia, breast cancer, bile duct cancer, brain cancer, chronic lymphocytic leukemia, colorectal carcinoma, esophageal cancer, gallbladder cancer, gastric cancer, hepatocellular cancer, non-Hodgkin lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small cell lung cancer, urinary bladder cancer and uterine cancer and other tumors that show an overexpression of a protein from which a peptide SEQ ID No. 1 to SEQ ID No. 237 is derived from.

22. A kit comprising: a) a container comprising a pharmaceutical composition containing the peptide(s) or the variant according to claim 1, an antibody or fragment thereof, a T-cell receptor or fragment thereof, an aptamer thereof, a nucleic acid or expression vector thereof, a host cell thereof, or an activated T lymphocyte thereof, in solution or in lyophilized form; b) optionally, a second container containing a diluent or reconstituting solution for the lyophilized formulation; c) optionally, at least one more peptides selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 338, and d) optionally, instructions for (i) use of the solution or (ii) reconstitution and/or use of the lyophilized formulation.

23. The kit according to claim 22, further comprising one or more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe.

24. A method for producing a personalized anti-cancer vaccine or a compound-based and/or cellular therapy for an individual patient, said method comprising: a) identifying tumor-associated peptides (TUMAPs) presented by a tumor sample from said individual patient; b) comparing the peptides as identified in a) with a warehouse of peptides comprising a plurality of peptides selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 338 and variants thereof that have been pre-screened for immunogenicity and/or over-presentation in tumors as compared to normal tissues; c) selecting at least one peptide from the warehouse that matches a TUMAP identified in the patient; and d) manufacturing and/or formulating the personalized vaccine or compound-based or cellular therapy based on step c).

25. The method according to claim 24, wherein said TUMAPs are identified by: a1) comparing expression data from the tumor sample to expression data from a sample of normal tissue corresponding to the tissue type of the tumor sample to identify proteins that are over-expressed or aberrantly expressed in the tumor sample; and a2) correlating the expression data with sequences of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample to identify MHC ligands derived from proteins over-expressed or aberrantly expressed by the tumor.

26. The method according to claim 24, wherein the sequences of MHC ligands are identified by eluting bound peptides from MHC molecules isolated from the tumor sample, and sequencing the eluted ligands.

27. The method according to claim 24, wherein the normal tissue corresponding to the tissue type of the tumor sample is obtained from the same patient.

28. The method according to claim 24, wherein the peptides included in the warehouse are identified based on the following steps: aa. Performing genome-wide messenger ribonucleic acid (mRNA) expression analysis by highly parallel methods, such as microarrays or sequencing-based expression profiling, comprising identify genes that over-expressed in a malignant tissue, compared with a normal tissue or tissues; ab. Selecting peptides encoded by selectively expressed or over-expressed genes as detected in step aa, and ac. Determining an induction of in vivo T-cell responses by the peptides as selected comprising in vitro immunogenicity assays using human T cells from healthy donors or said patient; or ba. Identifying HLA ligands from said tumor sample using mass spectrometry; bb. Performing genome-wide messenger ribonucleic acid (mRNA) expression analysis by highly parallel methods, such as microarrays or sequencing-based expression profiling, comprising identify genes that over-expressed in a malignant tissue, compared with a normal tissue or tissues; bc. Comparing the identified HLA ligands to said gene expression data; bd. Selecting peptides encoded by selectively expressed or over-expressed genes as detected in step bc; be. Re-detecting of selected TUMAPs from step bd on tumor tissue and lack of or infrequent detection on healthy tissues and confirming the relevance of over-expression at the mRNA level; and bf. Determining an induction of in vivo T-cell responses by the peptides as selected comprising in vitro immunogenicity assays using human T cells from healthy donors or said patient.

29. The method according claim 24, wherein the immunogenicity of the peptides included in the warehouse is determined by a method comprising in vitro immunogenicity assays, patient immunomonitoring for individual HLA binding, MHC multimer staining, ELISPOT assays and/or intracellular cytokine staining.

30. The method according to claim 24, wherein said warehouse comprises a plurality of peptides selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 338.

31. The method according to claim 24, further comprising identifying at least one mutation that is unique to the tumor sample relative to normal corresponding tissue from the individual patient, and selecting a peptide that correlates with the mutation for inclusion in the vaccine or for the generation of cellular therapies.

32. The method according to claim 31, wherein said at least one mutation is identified by whole genome sequencing.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0448] The present invention will now be described in the following examples which describe preferred embodiments thereof, and with reference to the accompanying figures, nevertheless, without being limited thereto. For the purposes of the present invention, all references as cited herein are incorporated by reference in their entireties.

[0449] FIGS. 1A through 1J show the over-presentation of various peptides in normal tissues (white bars) and melanoma (black bars). FIG. 1A) Gene symbol: S100A1, Peptide: FLDVKELML (SEQ ID NO.: 1), Tissues from left to right: 4 adipose tissues, 5 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 14 brains, 7 breasts, 7 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 20 large intestines, 23 livers, 49 lungs, 7 lymph nodes, 12 nerves, 2 ovaries, 8 pancreases, 6 parathyroid glands, 1 peritoneum, 5 pituitary glands, 7 placentas, 1 pleura, 3 prostates, 7 salivary glands, 5 skeletal muscles, 3 small intestines, 12 spleens, 5 stomachs, 5 testes, 2 thymi, 2 thyroid glands, 11 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 12 skins, 18 melanoma. FIG. 1B) Gene symbol: EXTL1, Peptide: VLFKDPVSV (SEQ ID NO.:3), Tissues from left to right: 4 adipose tissues, 5 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 14 brains, 7 breasts, 7 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 20 large intestines, 23 livers, 49 lungs, 7 lymph nodes, 12 nerves, 2 ovaries, 8 pancreases, 6 parathyroid glands, 1 peritoneum, 5 pituitary glands, 7 placentas, 1 pleura, 3 prostates, 7 salivary glands, 5 skeletal muscles, 3 small intestines, 12 spleens, 5 stomachs, 5 testes, 2 thymi, 2 thyroid glands, 11 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 12 skins, 18 melanoma. FIG. 1C) Gene symbol: HMCN1, Peptide: IQSETTVTV (SEQ ID NO.: 13), Tissues from left to right: 4 adipose tissues, 5 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 14 brains, 7 breasts, 7 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 20 large intestines, 23 livers, 49 lungs, 7 lymph nodes, 12 nerves, 2 ovaries, 8 pancreases, 6 parathyroid glands, 1 peritoneum, 5 pituitary glands, 7 placentas, 1 pleura, 3 prostates, 7 salivary glands, 5 skeletal muscles, 3 small intestines, 12 spleens, 5 stomachs, 5 testes, 2 thymi, 2 thyroid glands, 11 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 12 skins, 18 melanoma. FIG. 1D) Gene symbol: TMEM17, Peptide: NLQEKVPEL (SEQ ID NO.: 7), Samples from left to right: 14 cancer tissues (1 brain cancer, 1 breast cancer, 1 head-and-neck cancer, 3 lung cancers, 1 myeloid cells cancer, 1 ovarian cancer, 1 pancreas cancer, 4 melanomas, 1 uterus cancer). FIG. 1E) through 1J) show the over-presentation of various peptides in different cancer tissues (black dots). Upper part: Median MS signal intensities from technical replicate measurements are plotted as dots for single HLA-A*02 positive normal (grey dots) and tumor samples (black dots) on which the peptide was detected. Tumor and normal samples are grouped according to organ of origin, and box-and-whisker plots represent median, 25th and 75th percentile (box), and minimum and maximum (whiskers) of normalized signal intensities over multiple samples. Normal organs are ordered according to risk categories (blood cells, blood vessels, brain, liver, lung: high risk, grey dots; reproductive organs, breast, prostate: low risk, grey dots; all other organs: medium risk; grey dots). Lower part: The relative peptide detection frequency in every organ is shown as spine plot. Numbers below the panel indicate number of samples on which the peptide was detected out of the total number of samples analyzed for each organ (N=526 for normal samples, N=562 for tumor samples). If the peptide has been detected on a sample but could not be quantified for technical reasons, the sample is included in this representation of detection frequency, but no dot is shown in the upper part of the figure. Tissues (from left to right): Normal samples: blood cells; bloodvess (blood vessels); brain; heart; liver; lung; adipose (adipose tissue); adren.gl. (adrenal gland); bile duct; bladder; BM (bone marrow); cartilage; esoph (esophagus); eye; gallb (gallbladder); head&neck; kidney; large_int (large intestine); LN (lymph node); nerve; pancreas; parathyr (parathyroid gland); perit (peritoneum); pituit (pituitary); pleura; skel.mus (skeletal muscle); skin; small_int (small intestine); spleen; stomach; thyroid; trachea; ureter; breast; ovary; placenta; prostate; testis; thymus; uterus. Tumor samples: AML: acute myeloid leukemia; BRCA: breast cancer; CCC: cholangiocellular carcinoma; CLL: chronic lymphocytic leukemia; CRC: colorectal cancer; GBC: gallbladder cancer; GBM: glioblastoma; GC: gastric cancer; GEJC: stomach cardia esophagus, cancer; HCC: hepatocellular carcinoma; HNSCC: head-and-neck cancer; MEL: melanoma; NHL: non-hodgkin lymphoma; NSCLC: non-small cell lung cancer; OC: ovarian cancer; OSCAR: esophageal cancer; PACA: pancreatic cancer; PRCA: prostate cancer; RCC: renal cell carcinoma; SCLC: small cell lung cancer; UBC: urinary bladder carcinoma; UEC: uterine and endometrial cancer. FIG. 1E) Gene symbols: HLA-B, HLA-C, Peptide: VLAVLGAVVAV (SEQ ID NO.: 19), FIG. 1F) Gene symbol: PARVA, Peptide: SLVAILHLL (SEQ ID NO.: 24), FIG. 1G) Gene symbol: METAP2, Peptide: TMIEICEKL (SEQ ID NO.: 118), FIG. 1H) Gene symbol: UTP20, Peptide: QLMEGKVVL (SEQ ID NO.: 120), FIG. 1I) Gene symbol: SNRPN, Peptide: FLGEPASYLYL (SEQ ID NO.: 151), FIG. 1J) Gene symbol: IPO9, Peptide: SILDGLIHL (SEQ ID NO.: 209).

[0450] FIGS. 2A through 2C) show exemplary expression profiles of source genes of the present invention that are highly over-expressed or exclusively expressed in melanoma in a panel of normal tissues (white bars) and 10 melanoma samples (black bars). Tissues from left to right: 6 arteries, 2 blood cells, 2 brains, 1 heart, 2 livers, 3 lungs, 2 veins, 1 adipose tissue, 1 adrenal gland, 5 bone marrows, 1 cartilage, 1 colon, 1 esophagus, 2 eyes, 2 gallbladders, 2 head-and-neck and salivary glands, 1 kidney, 6 lymph nodes, 4 pancreases, 2 peripheral nerves, 2 pituitary glands, 1 rectum, 2 skeletal muscles, 1 skin, 1 small intestine, 1 spleen, 1 stomach, 1 thyroid gland, 7 tracheas, 1 urinary bladder, 1 breast, 5 ovaries, 5 placentas, 1 prostate, 1 testis, 1 thymus, 1 uterus, 10 melanoma. FIG. 2A) Gene symbol: SLC24A5, FIG. 2B) Gene symbol: SLC45A2, FIG. 2C) Gene symbol: FMN1.

[0451] FIG. 3 shows exemplary immunogenicity data: flow cytometry results after peptide-specific multimer staining.

[0452] FIG. 4 show exemplary results of peptide-specific in vitro CD8+ T cell responses of a healthy HLA-A*02+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*02 in complex with SeqID No 8 peptide (A, left panel), SeqID No 12 peptide (B, left panel) and SeqID No 155 peptide (C, left panel), respectively. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D multimer staining with A*02/SeqID No 8 (A), A*02/SeqID No 12 (B) or A*02/SeqID No 155 (C). Right panels (A, B and C) show control staining of cells stimulated with irrelevant A*02/peptide complexes. Viable singlet cells were gated for CD8+ lymphocytes. Boolean gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of specific multimer+ cells among CD8+ lymphocytes are indicated.

EXAMPLES

Example 1

Identification and Quantitation of Tumor Associated Peptides Presented on the Cell Surface

Tissue Samples

[0453] Patients' tumor tissues were obtained from: Asterand (Detroit, Mich., USA & Royston, Herts, UK); ProteoGenex Inc. (Culver City, Calif., USA), Tissue Solutions Ltd (Glasgow, UK); University Hospital Heidelberg (Heidelberg, Germany); and University Hospital Tübingen (Tübingen, Germany).

[0454] Normal tissues were obtained from Asterand (Detroit, Mich., USA & Royston, Herts, UK); Bio-Options Inc. (Brea, Calif., USA); BioServe (Beltsville, Md., USA); Capital BioScience Inc. (Rockville, Md., USA); Geneticist Inc. (Glendale, Calif., USA); Kyoto Prefectural University of Medicine (KPUM) (Kyoto, Japan); ProteoGenex Inc. (Culver City, Calif., USA); Tissue Solutions Ltd (Glasgow, UK); University Hospital Geneva (Geneva, Switzerland); University Hospital Heidelberg (Heidelberg, Germany); University Hospital Munich (Munich, Germany); and University Hospital Tübingen (Tübingen, Germany).

[0455] Written informed consents of all patients had been given before surgery or autopsy. Tissues were shock-frozen immediately after excision and stored until isolation of TUMAPs at −70° C. or below.

Isolation of HLA Peptides from Tissue Samples

[0456] HLA peptide pools from shock-frozen tissue samples were obtained by immune precipitation from solid tissues according to a slightly modified protocol (Falk et al., 1991; Seeger et al., 1999) using the HLA-A*02-specific antibody BB7.2, the HLA-A, —B, C-specific antibody W6/32, CNBr-activated sepharose, acid treatment, and ultrafiltration.

Mass Spectrometry Analyses

[0457] The HLA peptide pools as obtained were separated according to their hydrophobicity by reversed-phase chromatography (nanoAcquity UPLC system, Waters) and the eluting peptides were analyzed in LTQ-velos and fusion hybrid mass spectrometers (ThermoElectron) equipped with an ESI source. Peptide pools were loaded directly onto the analytical fused-silica micro-capillary column (75 μm i.d.×250 mm) packed with 1.7 μm C18 reversed-phase material (Waters) applying a flow rate of 400 nL per minute. Subsequently, the peptides were separated using a two-step 180 minute-binary gradient from 10% to 33% B at a flow rate of 300 nL per minute. The gradient was composed of Solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile). A gold coated glass capillary (PicoTip, New Objective) was used for introduction into the nanoESI source. The LTQ-Orbitrap mass spectrometers were operated in the data-dependent mode using a TOP5 strategy. In brief, a scan cycle was initiated with a full scan of high mass accuracy in the Orbitrap (R=30 000), which was followed by MS/MS scans also in the Orbitrap (R=7500) on the 5 most abundant precursor ions with dynamic exclusion of previously selected ions. Tandem mass spectra were interpreted by SEQUEST and additional manual control. The identified peptide sequence was assured by comparison of the generated natural peptide fragmentation pattern with the fragmentation pattern of a synthetic sequence-identical reference peptide.

[0458] Label-free relative LC-MS quantitation was performed by ion counting i.e. by extraction and analysis of LC-MS features (Mueller et al., 2007). The method assumes that the peptide's LC-MS signal area correlates with its abundance in the sample. Extracted features were further processed by charge state deconvolution and retention time alignment (Mueller et al., 2008; Sturm et al., 2008). Finally, all LC-MS features were cross-referenced with the sequence identification results to combine quantitative data of different samples and tissues to peptide presentation profiles. The quantitative data were normalized in a two-tier fashion according to central tendency to account for variation within technical and biological replicates. Thus each identified peptide can be associated with quantitative data allowing relative quantification between samples and tissues. In addition, all quantitative data acquired for peptide candidates was inspected manually to assure data consistency and to verify the accuracy of the automated analysis. For each peptide a presentation profile was calculated showing the mean sample presentation as well as replicate variations. The profiles juxtapose melanoma samples to a baseline of normal tissue samples. Presentation profiles of exemplary over-presented peptides are shown in FIGS. 1A-1J. Presentation scores for exemplary peptides are shown in Table 8.

TABLE-US-00009 TABLE 8 Presentation scores. The table lists peptides that are very highly over-presented on tumors compared to a panel of normal tissues (+++), highly over-presented on tumors compared to a panel of normal tissues (++) or over-presented on tumors compared to a panel of normal tissues (+). The panel of normal tissues considered relevant for comparison with tumors consisted of: adipose tissue, adrenal gland, artery, vein, bone marrow, brain, central and peripheral nerve, colon, rectum, small intestine incl. duodenum, esophagus, eye, gallbladder, heart, kidney, liver, lung, lymph node, mononuclear white blood cells, pancreas, parathyroid gland, peritoneum, pituitary, pleura, salivary gland, skeletal muscle, skin, spleen, stomach, thymus, thyroid gland, trachea, ureter, urinary bladder. SEQ ID Peptide No. Sequence Presentation 1 LLSGQLPTI +++ 2 LLSEETPSA +++ 3 LTIDTQYYL +++ 5 VLQGLTFTL +++ 6 TLITLPLLFL +++ 7 NLLGMIFSM +++ 8 ALYAVIEKA +++ 9 FLLDLDPLL +++ 10 FLLVGTQIDL +++ 11 GLDTVVALL +++ 12 GLLLLVPLL +++ 13 HLVPASWKL +++ 15 IIIEDLLEA +++ 16 TLIAAILYL +++ 17 VIIPLLSSV +++ 18 KLTDQPPLV +++ 19 VLEAILPLV +++ 20 YLIAGGDRWL +++ 21 ALFKEAYSL +++ 22 ALKKHLTSV +++ 23 ALVEDIINL +++ 24 AVLGFSFRL +++ 25 FLDTSNQHLL +++ 26 FLGSFIDHV +++ 27 FLNQESFDL +++ 28 FLSNANPSL +++ 29 ILSDVTQGL +++ 30 ILSTLDVEL +++ 31 KLYDEESLL +++ 32 VLNEDELPSV +++ 33 LLANIVPIAMLV +++ 34 LLWEDGVTEA +++ 35 SLSSERYYL +++ 36 VILDIPLLFET +++ 37 VLGNALEGV +++ 38 YLTAEILELAGN +++ 40 FLNSVIVDL + 41 ILASIFETV +++ 43 ALLEGVKNV + 44 FIIEEQSFL +++ 45 FILDDSALYL + 46 FLVEEIFQT ++ 47 GLLPKLTAL + 49 TILGDPQILL +++ 50 LLLDGLIYL + 53 FLREYFERL +++ 54 DIFDAMFSV +++ 55 ILVEVDLVQA ++ 56 GLQDLLFSL ++ 57 LQIGDFVSV + 60 SLLIDVITV +++ 61 SLLNKDLSL + 62 ALAPYLDLL +++ 64 FLVEVSNDV ++ 65 NLTDVSPDL +++ 67 LLATVNVAL +++ 69 TLLAFPLLL + 71 VLLDYVGNVQL +++ 72 TLQEETAVYL +++ 74 SLDLRPLEV + 75 AALKYIPSV +++ 76 ALADLVPVDVVV +++ 77 ALLDVSNNYGI +++ 78 AMEEAVAQV +++ 79 AMKEEKEQL +++ 80 YLFDEIDQA +++ 81 FIFSYITAV +++ 82 FLIDGSSSV +++ 83 FLMDDNMSNTL +++ 84 FLQELQLEHA +++ 85 GLAPAEVVVATVA +++ 86 GLATIRAYL +++ 87 GLFARIIMI +++ 88 GLFDNRSGLPEA +++ 89 GLTALHVAV +++ 90 HLDEVFLEL +++ 91 HLSSTTAQV +++ 92 KLLFEIASA +++ 93 KLLGSLQLL +++ 94 LLAGQATTAYF +++ 95 LLFDLIPVVSV +++ 96 LLLNENESLFL +++ 97 LLNFSPGNL +++ 98 MLQDGIARL +++ 99 QLYDGATALFL +++ 100 RLIRTIAAI +++ 101 SLDQSTWNV +++ 102 SLFAAISGMIL +++ 103 SLQDHLEKV +++ 104 VLLGLPLLV +++ 105 VLTPVILQV +++ 106 VLYELLQYI +++ 107 VQAVSIPEV +++ 108 YLAPENGYLM +++ 109 YLFQFSAAL +++ 110 YQYPFVLGL +++ 111 YLLDTLLSL +++ 112 FLAILPEEV +++ 113 FVIDSFEEL +++ 114 GLSDISPST +++ 115 LLIDIIHFL +++ 116 SLLDNLLTI + 117 VLATILAQL +++ 118 VLDGMIYAI +++ 119 ELCDIILRV +++ 120 VLLGTTWAL +++ 121 YLTGYNFTL +++ 122 AISEAQESV + 123 ALLSAFVQL ++ 124 FLGVVVPTV +++ 125 FVAPPTAAV +++ 126 GLSIFIYRL +++ 128 KLFDASPTFFA ++ 131 VLIEETDQL +++ 132 VLQDQVDEL +++ 133 ALEELTGFREL +++ 134 ALGRLGILSV +++ 135 ALTGLQFQL +++ 136 FIFGIVHLL +++ 137 FIQQERFFL +++ 138 NLINNIFEL + 139 FLASPLVAI +++ 140 FLFEDFVEV +++ 141 FLGELTLQL +++ 142 FLYEDSKSVRL +++ 143 TLHAVDVTL +++ 144 GLITQVDKL +++ 145 GLLHEVVSL +++ 146 GLLQQPPAL +++ 147 GLSEYQRNFL +++ 148 ICAGHVPGV +++ 149 ILNPVTTKL +++ 150 ILSEKEYKL +++ 151 ILVKQSPML +++ 152 KIMYTLVSV +++ 153 KLLKGIYAI +++ 154 KLMNIQQQL +++ 155 KLMTSLVKV +++ 156 KMLEDDLKL +++ 157 KVLEFLAKV +++ 158 KVQDVLHQV +++ 159 LLLSDSGFYL +++ 160 LLPPPSPAA +++ 161 NLMLELETV +++ 162 RLADLKVSI +++ 163 SIFDAVLKGV +++ 164 SLFDGAVISTV +++ 165 KLLEEIEFL ++ 166 SLFSEVASL +++ 167 SLFSITKSV +++ 168 SLLSPLLSV +++ 169 SSLEENLLHQV +++ 170 STIELSENSL +++ 171 TLLDVISAL +++ 172 TLQDSLEFI +++ 173 VILDSVASV +++ 174 VLVEITDVDFAA +++ 175 VMESILLRL +++ 176 YLHIYESQL +++ 177 YLYEAEEATTL +++ 178 YVLQGEFFL +++ 179 FVDTNLYFL +++ 180 GILQLVESV ++ 182 LLPPPPPVA + 183 VLFETVLTI + 185 FIAQLNNVEL + 186 FLDVSRDFV + 188 GLEDEMYEV ++ 189 SLSHLVPAL + 190 GLIELVDQL ++ 191 GLSDISAQV +++ 194 SLAPFDREPFTL +++ 195 ALIPDLNQI +++ 196 TLALAMIYL ++ 200 YLLDFEDRL + 201 YLNISQVNV ++ 203 ILDTIFHKV +++ 204 RLCDIVVNV +++ 207 GLVGLLEQA ++ 211 FIDDLFAFV +++ 212 FLIGQGAHV + 213 YINEDEYEV + 214 FLFDGSMSL ++ 215 QLFEEEIEL + 216 KVVSNLPAI +++ 217 AQFGAVLEV + 218 ALDQFLEGI + 219 ALLELENSV +++ 220 FLAEAPTAL ++ 221 FLAPDNSLLLA +++ 222 FLIETGTLL + 224 FLSPLLPLL + 225 GTYQDVGSLNIGDV +++ 226 GVIDPVPEV + 227 IIAEGIPEA + 231 IVMGAIPSV + 232 KVMEGTVAA ++ 233 MLEVHIPSV ++ 236 SLFDGFFLTA + 237 YLDRLIPQA ++ 239 VLIDDTVLL ++ 242 GILDFZVFL + 243 GLPDLDIYL +++ 244 ILEPFLPAV + 246 KLPVPLESV + 249 VLLESLVEI +++ 252 YLGDLIMAL + 253 YSDDDVPSV +++ 254 FLYSETWNI +++ 255 GMWNPNAPVFL +++ 256 ALQETPPQV +++ 257 FLQEWEVYA +++ 258 RIYPFLLMV +++ 259 TVLDGLEFKV +++ 260 RLDEAFDFV ++ 263 GLMDNEIKV +++ 264 ILTGTPPGV +++ 265 ILWHFVASL +++ 266 QLTEMLPSI +++ 267 SLLETGSDLLL +++ 268 VLFPLPTPL +++ 269 VLQNVAFSV +++ 270 VVVDSDSLAFV +++ 271 YLLDQPVLEQRL +++ 272 KLDHTLSQI +++ 273 AILLPQPPK +++ 274 KLLNLISKL +++ 275 KLMDLEDCAL +++ 276 NMISYVVHL +++ 277 FLIDLNSTHGTFL + 279 NLAGENILNPL ++ 280 SLLNHLPYL +++ 285 SITAVTPLL + 287 ILMGHSLYM ++ 289 SLLAANNLL +++ 290 IASPVIAAV +++ 291 KIIDTAGLSEA +++ 292 KLINSQISL ++ 294 KLYGPEGLELV + 296 FILEPLYKI ++ 298 ALTDVILCV + 299 RLLEEEGVSL + 302 SLAELDEKISA + 303 FVWEASHYL ++ 305 AMLAQQMQL + 307 FLLPVAVKL ++ 308 SLLDQIPEM +

Example 2

Expression Profiling of Genes Encoding the Peptides of the Invention

[0459] Over-presentation or specific presentation of a peptide on tumor cells compared to normal cells is sufficient for its usefulness in immunotherapy, and some peptides are tumor-specific despite their source protein occurring also in normal tissues. Still, mRNA expression profiling adds an additional level of safety in selection of peptide targets for immunotherapies. Especially for therapeutic options with high safety risks, such as affinity-matured TCRs, the ideal target peptide will be derived from a protein that is unique to the tumor and not found on normal tissues.

RNA Sources and Preparation

[0460] Surgically removed tissue specimens were provided as indicated above (see Example 1) after written informed consent had been obtained from each patient. Tumor tissue specimens were snap-frozen immediately after surgery and later homogenized with mortar and pestle under liquid nitrogen. Total RNA was prepared from these samples using TRI Reagent (Ambion, Darmstadt, Germany) followed by a cleanup with RNeasy (QIAGEN, Hilden, Germany); both methods were performed according to the manufacturer's protocol.

[0461] Total RNA from healthy human tissues for RNASeq experiments was obtained from: Asterand (Detroit, Mich., USA & Royston, Herts, UK); BioCat GmbH (Heidelberg, Germany); BioServe (Beltsville, Md., USA), Capital BioScience Inc. (Rockville, Md., USA); Geneticist Inc. (Glendale, Calif., USA), Istituto Nazionale Tumori “Pascale” (Naples, Italy); ProteoGenex Inc. (Culver City, Calif., USA), and University Hospital Heidelberg (Heidelberg, Germany).

[0462] Total RNA from tumor tissues for RNASeq experiments was obtained from: Asterand (Detroit, Mich., USA & Royston, Herts, UK); ProteoGenex Inc. (Culver City, Calif., USA); Tissue Solutions Ltd (Glasgow, UK), and University Hospital Tübingen (Tübingen, Germany).

[0463] Quality and quantity of all RNA samples were assessed on an Agilent 2100 Bioanalyzer (Agilent, Waldbronn, Germany) using the RNA 6000 Pico LabChip Kit (Agilent).

RNAseq Experiments

[0464] Gene expression analysis of—tumor and normal tissue RNA samples was performed by next generation sequencing (RNAseq) by CeGaT (Tübingen, Germany). Briefly, sequencing libraries are prepared using the Illumina HiSeq v 4 reagent kit according to the provider's protocol (Illumina Inc., San Diego, Calif., USA), which includes RNA fragmentation, cDNA conversion and addition of sequencing adaptors. Libraries derived from multiple samples are mixed equimolar and sequenced on the Illumina HiSeq 2500 sequencer according to the manufacturer's instructions, generating 50 bp single end reads. Processed reads are mapped to the human genome (GRCh38) using the STAR software. Expression data are provided on transcript level as RPKM (Reads Per Kilobase per Million mapped reads, generated by the software Cufflinks) and on exon level (total reads, generated by the software Bedtools), based on annotations of the ensembl sequence database (Ensembl77). Exon reads are normalized for exon length and alignment size to obtain RPKM values. Exemplary expression profiles of source genes of the present invention that are highly over-expressed or exclusively expressed in melanoma are shown in FIGS. 2A-2C. Expression scores for further exemplary genes are shown in Table 9.

TABLE-US-00010 TABLE 9 Expression scores. The table lists peptides from genes that are very highly over-expressed in tumors compared to a panel of normal tissues (+++), highly over-expressed in tumors compared to a panel of normal tissues (++) or over- expressed in tumors compared to a panel of normal tissues (+). The baseline for this score was calculated from measurements of the following relevant normal tissues: adipose tissue, adrenal gland, artery, blood cells, bone marrow, brain, cartilage, colon, esophagus, eye, gallbladder, heart, kidney, liver, lung, lymph node, pancreas,  pituitary, rectum, salivary gland, skeletal muscle, skin, small intestine, spleen, stomach, thyroid gland, trachea, urinary bladder, and vein. In case expression data for several samples of the same tissue type were available, the arithmetic mean of all respective samples was used for the calculation. Gene SEQ ID No Sequence Expression   9 FLLDLDPLL ++  21 ALFKEAYSL +  25 FLDTSNQHLL ++  30 ILSTLDVEL ++  38 YLTAEILELAGN ++  43 ALLEGVKNV +  55 ILVEVDLVQA +  56 GLQDLLFSL +  61 SLLNKDLSL +  91 HLSSTTAQV ++ 102 SLFAAISGMIL +++ 106 VLYELLQYI +++ 112 FLAILPEEV ++ 113 FVIDSFEEL +++ 116 SLLDNLLTI + 133 ALEELTGFREL + 135 ALTGLQFQL +++ 142 FLYEDSKSVRL +++ 143 TLHAVDVTL +++ 146 GLLQQPPAL + 148 ICAGHVPGV +++ 155 KLMTSLVKV +++ 157 KVLEFLAKV +++ 158 KVQDVLHQV +++ 159 LLLSDSGFYL ++ 160 LLPPPSPAA +++ 161 NLMLELETV +++ 162 RLADLKVSI +++ 167 SLFSITKSV +++ 170 STIELSENSL ++ 174 VLVEITDVDFAA + 175 VMESILLRL +++ 178 YVLQGEFFL +++ 183 VLFETVLTI + 192 GMAAEVPKV + 199 SLNSTTWKV +++ 202 ALAAGGYDV +++ 222 FLIETGTLL ++ 225 GTYQDVGSLNIGDV ++ 229 ILSPWGAEV ++ 238 YQYGAVVTL ++ 256 ALQETPPQV + 260 RLDEAFDFV ++ 268 VLFPLPTPL + 276 NMISYVVHL +++ 294 KLYGPEGLELV +++ 297 ILQNGLETL +++ 298 ALTDVILCV +++

Example 3

In Vitro Immunogenicity for MHC Class I Presented Peptides

[0465] In order to obtain information regarding the immunogenicity of the TUMAPs of the present invention, the inventors performed investigations using an in vitro T-cell priming assay based on repeated stimulations of CD8+ T cells with artificial antigen presenting cells (aAPCs) loaded with peptide/MHC complexes and anti-CD28 antibody. This way the inventors could show immunogenicity for HLA-A*0201 restricted TUMAPs of the invention, demonstrating that these peptides are T-cell epitopes against which CD8+ precursor T cells exist in humans (Table 10).

In Vitro Priming of CD8+ T Cells

[0466] In order to perform in vitro stimulations by artificial antigen presenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28 antibody, the inventors first isolated CD8+ T cells from fresh HLA-A*02 leukapheresis products via positive selection using CD8 microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtained from the University clinics Mannheim, Germany, after informed consent.

[0467] PBMCs and isolated CD8+ lymphocytes were incubated in T-cell medium (TCM) until use consisting of RPMI-Glutamax (Invitrogen, Karlsruhe, Germany) supplemented with 10% heat inactivated human AB serum (PAN-Biotech, Aidenbach, Germany), 100 U/ml Penicillin/100 μg/ml Streptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro, Oberdorla, Germany), 20 μg/ml Gentamycin (Cambrex). 2.5 ng/ml IL-7 (PromoCell, Heidelberg, Germany) and 10 U/ml IL-2 (Novartis Pharma, Nürnberg, Germany) were also added to the TCM at this step.

[0468] Generation of pMHC/anti-CD28 coated beads, T-cell stimulations and readout was performed in a highly defined in vitro system using four different pMHC molecules per stimulation condition and 8 different pMHC molecules per readout condition.

[0469] The purified co-stimulatory mouse IgG2a anti human CD28 Ab 9.3 (Jung et al., 1987) was chemically biotinylated using Sulfo-N-hydroxysuccinimidobiotin as recommended by the manufacturer (Perbio, Bonn, Germany). Beads used were 5.6 μm diameter streptavidin coated polystyrene particles (Bangs Laboratories, Illinois, USA).

[0470] pMHC used for positive and negative control stimulations were A*0201/MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 339) from modified Melan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5, SEQ ID NO. 340), respectively.

[0471] 800.000 beads/200 μl were coated in 96-well plates in the presence of 4×12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 were added subsequently in a volume of 200 μl. Stimulations were initiated in 96-well plates by co-incubating 1×10.sup.6 CD8+ T cells with 2×10.sup.6 washed coated beads in 200 μl TCM supplemented with 5 ng/ml IL-12 (PromoCell) for 3 days at 37° C. Half of the medium was then exchanged by fresh TCM supplemented with 80 U/ml IL-2 and incubating was continued for 4 days at 37° C. This stimulation cycle was performed for a total of three times. For the pMHC multimer readout using 8 different pMHC molecules per condition, a two-dimensional combinatorial coding approach was used as previously described (Andersen et al., 2012) with minor modifications encompassing coupling to 5 different fluorochromes. Finally, multimeric analyses were performed by staining the cells with Live/dead near IR dye (Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD, Heidelberg, Germany) and fluorescent pMHC multimers. For analysis, a BD LSRII SORP cytometer equipped with appropriate lasers and filters was used. Peptide specific cells were calculated as percentage of total CD8+ cells. Evaluation of multimeric analysis was done using the FlowJo software (Tree Star, Oregon, USA). In vitro priming of specific multimer+CD8+ lymphocytes was detected by comparing to negative control stimulations. Immunogenicity for a given antigen was detected if at least one evaluable in vitro stimulated well of one healthy donor was found to contain a specific CD8+ T-cell line after in vitro stimulation (i.e. this well contained at least 1% of specific multimer+ among CD8+ T-cells and the percentage of specific multimer+ cells was at least 10× the median of the negative control stimulations).

In Vitro Immunogenicity for Melanoma Peptides

[0472] For tested HLA class I peptides, in vitro immunogenicity could be demonstrated by generation of peptide specific T-cell lines. Exemplary flow cytometry results after TUMAP-specific multimer staining for 2 peptides of the invention are shown in FIG. 3 together with corresponding negative controls. Additional exemplary flow cytometry results after TUMAP-specific multimer staining for 3 peptides of the invention are shown in FIG. 4 together with corresponding negative controls. Results for 33 peptides from the invention are summarized in Table 10A. Additional results for 29 peptides from the invention are summarized in Table 10B.

TABLE-US-00011 TABLE 10A in vitro immunogenicity of HLA class I peptides of the invention  Exemplary results of in vitro immunogenicity experiments conducted by the applicant for the  peptides of the invention. <20% = +; 20%-49% = ++; 50 -69% = +++; > = 70% = ++++ Seq ID Sequence wells 319 SLYKGLLSV ++ 320 LLWGNLPEI ++ 321 KLLAVIHEL ++ 322 TLTNIIHNL ++ 323 ILVDWLVQV ++ 324 LLYDAVHIV ++ 325 FLFVDPELV +++ 326 KLTDVGIATL ++++ 327 MLFGHPLLVSV ++ 328 ILFPDIIARA ++++

TABLE-US-00012 TABLE 10B In vitro immunogenicity of HLA class I peptides  of the invention Exemplary results of in vitro immunogenicity experiments conducted by the applicant for HLA-A*02 restricted peptides of the invention. Results of in vitro immunogenicity experiments are indicated. Percentage of positive wells and donors (among evaluable) are summarized as indicated <20% = +; 20%-49% = ++; 50%-69 = +++; > =70% = ++++ SEQ ID NO: Sequence Wells positive [%]   1 LLSGQLPTI ″+++″   2 LLSEETPSA ″+″   3 LTIDTQYYL ″+″   5 VLQGLTFTL ″+++″   7 NLLGMIFSM ″++++″   8 ALYAVIEKA ″+″   9 FLLDLDPLL ″++″  12 GLLLLVPLL ″+++″  13 HLVPASWKL ″+++″  17 VIIPLLSSV ″++″  19 VLEAILPLV ″+″  21 ALFKEAYSL ″+″  22 ALKKHLTSV ″++++″  24 AVLGFSFRL ″++++″  25 FLDTSNQHLL ″+″  26 FLGSFIDHV ″+″  27 FLNQESFDL ″+″  28 FLSNANPSL ″++++″  29 ILSDVTQGL ″+″  30 ILSTLDVEL ″++″  33 LLANIVPIAMLV ″+″  35 SLSSERYYL ″++++″  36 VILDIPLLFET ″++″  37 VLGNALEGV ″+″  40 FLNSVIVDL ″+++″  41 ILASIFETV ″+++″  42 YLQDLVERA ″+++″  43 ALLEGVKNV ″++″  44 FIIEEQSFL ″+″  46 FLVEEIFQT ″+″  47 GLLPKLTAL ″++″  51 SLLGNSPVL ″+++″  52 VLLEDVDAAFL ″+″  53 FLREYFERL ″+++″  57 LQIGDFVSV ″++++″  59 RLHREVAQV ″+″  60 SLLIDVITV ″+++″  61 SLLNKDLSL ″+″  62 ALAPYLDLL ″++″  66 KLAPIPVEL ″++″  67 LLATVNVAL ″+″  68 QIAAFLFTV ″+++″  73 YLGEEYPEV ″+″  74 SLDLRPLEV ″++″ 253 YSDDDVPSV ″+++″ 254 FLYSETWNI ″+″ 256 ALQETPPQV ″+″ 258 RIYPFLLMV ″++++″ 260 RLDEAFDFV ″++++″ 261 FLPETRIMTSV ″+″ 262 LMGPVVHEV ″++″

Example 4

Synthesis of Peptides

[0473] All peptides were synthesized using standard and well-established solid phase peptide synthesis using the Fmoc-strategy. Identity and purity of each individual peptide have been determined by mass spectrometry and analytical RP-HPLC. The peptides were obtained as white to off-white lyophilizes (trifluoro acetate salt) in purities of >50%. All TUMAPs are preferably administered as trifluoro-acetate salts or acetate salts, other salt-forms are also possible.

Example 5

MHC Binding Assays

[0474] Candidate peptides for T cell based therapies according to the present invention were further tested for their MHC binding capacity (affinity). The individual peptide-MHC complexes were produced by UV-ligand exchange, where a UV-sensitive peptide is cleaved upon UV-irradiation, and exchanged with the peptide of interest as analyzed. Only peptide candidates that can effectively bind and stabilize the peptide-receptive MHC molecules prevent dissociation of the MHC complexes. To determine the yield of the exchange reaction, an ELISA was performed based on the detection of the light chain (β2m) of stabilized MHC complexes. The assay was performed as generally described in Rodenko et al. (Rodenko et al., 2006).

[0475] 96 well MAXISorp plates (NUNC) were coated over night with 2 ug/ml streptavidin in PBS at room temperature, washed 4× and blocked for 1 h at 37° C. in 2% BSA containing blocking buffer. Refolded HLA-A*02:01/MLA-001 monomers served as standards, covering the range of 15-500 ng/ml. Peptide-MHC monomers of the UV-exchange reaction were diluted 100 fold in blocking buffer. Samples were incubated for 1 h at 37° C., washed four times, incubated with 2 ug/ml HRP conjugated anti-β2m for 1 h at 37° C., washed again and detected with TMB solution that is stopped with NH.sub.2SO.sub.4. Absorption was measured at 450 nm. Candidate peptides that show a high exchange yield (preferably higher than 50%, most preferred higher than 75%) are generally preferred for a generation and production of antibodies or fragments thereof, and/or T cell receptors or fragments thereof, as they show sufficient avidity to the MHC molecules and prevent dissociation of the MHC complexes.

TABLE-US-00013 TABLE 11 MHC class I binding scores. Binding of HLA-class I restricted peptides to HLA-A*02:01 was ranged by peptide exchange yield: ≧10% = +; ≧20% = ++; ≧50 = +++; ≧75% = ++++ SEQ ID NO: Sequence Peptide exchange   1 LLSGQLPTI ″+++″   2 LLSEETPSA ″+++″   3 LTIDTQYYL ″+++″   4 TLLGFFLAKV ″++″   5 VLQGLTFTL ″+++″   6 TLITLPLLFL ″+++″   7 NLLGMIFSM ″++++″   8 ALYAVIEKA ″+++″   9 FLLDLDPLL ″+++″  10 FLLVGTQIDL ″+++″  11 GLDTVVALL ″+++″  12 GLLLLVPLL ″+++″  13 HLVPASWKL ″+++″  14 LLSDPTPGA ″++″  15 IIIEDLLEA ″++++″  16 TLIAAILYL ″++″  17 VIIPLLSSV ″+++″  18 KLTDQPPLV ″+++″  19 VLEAILPLV ″++++″  21 ALFKEAYSL ″+++″  22 ALKKHLTSV ″+++″  23 ALVEDIINL ″++++″  24 AVLGFSFRL ″+++″  25 FLDTSNQHLL ″+++″  26 FLGSFIDHV ″+++″  27 FLNQESFDL ″+++″  28 FLSNANPSL ″+++″  29 ILSDVTQGL ″+++″  30 ILSTLDVEL ″+++″  31 KLYDEESLL ″++++″  32 VLNEDELPSV ″+++″  33 LLANIVPIAMLV ″++++″  34 LLWEDGVTEA ″+++″  35 SLSSERYYL ″+++″  36 VILDIPLLFET ″+++″  37 VLGNALEGV ″+++″  38 YLTAEILELAGN ″++″  39 QLLPQGIVPAL ″+++″  40 FLNSVIVDL ″++++″  41 ILASIFETV ″++++″  42 YLQDLVERA ″++++″  43 ALLEGVKNV ″+++″  44 FIIEEQSFL ″+++″  45 FILDDSALYL ″+++″  46 FLVEEIFQT ″+++″  47 GLLPKLTAL ″+++″  48 KILDEDLYI ″+++″  49 TILGDPQILL ″++++″  50 LLLDGLIYL ″+++″  51 SLLGNSPVL ″++++″  52 VLLEDVDAAFL ″++++″  53 FLREYFERL ″++++″  54 DIFDAMFSV ″+++++″  55 ILVEVDLVQA ″++++″  56 GLQDLLFSL ″+++″  57 LQIGDFVSV ″++++″  58 QLAPFLPQL ″+++″  59 RLHREVAQV ″+++″  60 SLLIDVITV ″+++″  61 SLLNKDLSL ″++++″  62 ALAPYLDLL ″++++″  63 ALIEEAYGL ″+++″  64 FLVEVSNDV ″++++″  65 NLTDVSPDL ″+++″  66 KLAPIPVEL ″++++″  67 LLATVNVAL ″++++″  68 QIAAFLFTV ″++++″  69 TLLAFPLLL ″++++″  70 VLIEILQKA ″++++″  71 VLLDYVGNVQL ″++++″  72 TLQEETAVYL ″++″  73 YLGEEYPEV ″+++″  74 SLDLRPLEV ″++++″  75 AALKYIPSV ″+++″  76 ALADLVPVDVVV ″++++″  77 ALLDVSNNYGI ″++++″  78 AMEEAVAQV ″+++″  79 AMKEEKEQL ″++″  80 YLFDEIDQA ″+++″  81 FIFSYITAV ″++″  82 FLIDGSSSV ″+++″  83 FLMDDNMSNTL ″+++″  84 FLQELQLEHA ″+++″  85 GLAPAEVVVATVA ″+++″  86 GLATIRAYL ″+++″  87 GLFARIIMI ″++″  88 GLFDNRSGLPEA ″+++″  89 GLTALHVAV ″+++″  90 HLDEVFLEL ″+++″  91 HLSSTTAQV ″++″  92 KLLFEIASA ″+++″  93 KLLGSLQLL ″++++″  94 LLAGQATTAYF ″+++″  95 LLFDLIPVVSV ″+++″  96 LLLNENESLFL ″+++″  97 LLNFSPGNL ″+″  98 MLQDGIARL ″+++″  99 QLYDGATALFL ″++″ 100 RLIRTIAAI ″+++″ 101 SLDQSTWNV ″++++″ 102 SLFAAISGMIL ″+++″ 103 SLQDHLEKV ″+++″ 104 VLLGLPLLV ″+++″ 105 VLTPVILQV ″+++″ 106 VLYELLQYI ″++++″ 107 VQAVSIPEV ″+++″ 108 YLAPENGYLM ″+++″ 109 YLFQFSAAL ″+++″ 110 YQYPFVLGL ″++++″ 111 YLLDTLLSL ″+++″ 112 FLAILPEEV ″+++″ 113 FVIDSFEEL ″+++″ 114 GLSDISPST ″++″ 115 LLIDIIHFL ″++++″ 116 SLLDNLLTI ″+++″ 117 VLATILAQL ″++++″ 118 VLDGMIYAI ″+++″ 119 ELCDIILRV ″+++″ 120 VLLGTTWAL ″+++″ 121 YLTGYNFTL ″+++″ 122 AISEAQESV ″++″ 123 ALLSAFVQL ″+++″ 124 FLGVVVPTV ″+++″ 125 FVAPPTAAV ″+++″ 127 HLMEENMIVYV ″+++″ 128 KLFDASPTFFA ″+++″ 129 SLFEASQQL ″+++″ 130 VIFSYVLGV ″+++″ 131 VLIEETDQL ″++″ 132 VLQDQVDEL ″++″ 133 ALEELTGFREL ″++″ 134 ALGRLGILSV ″+++″ 135 ALTGLQFQL ″+++″ 136 FIFGIVHLL ″+++″ 137 FIQQERFFL ″+++″ 138 NLINNIFEL ″++++″ 139 FLASPLVAI ″++++″ 140 FLFEDFVEV ″+++″ 141 FLGELTLQL ″+++″ 142 FLYEDSKSVRL ″+++″ 143 TLHAVDVTL ″+++″ 144 GLITQVDKL ″+++″ 145 GLLHEVVSL ″+++″ 146 GLLQQPPAL ″+++″ 147 GLSEYQRNFL ″+++″ 148 ICAGHVPGV ″+++″ 149 ILNPVTTKL ″+++″ 150 ILSEKEYKL ″+++″ 151 ILVKQSPML ″+++″ 152 KIMYTLVSV ″++″ 153 KLLKGIYAI ″+++″ 154 KLMNIQQQL ″+++″ 155 KLMTSLVKV ″+++″ 156 KMLEDDLKL ″+++″ 157 KVLEFLAKV ″+++″ 158 KVQDVLHQV ″+++″ 159 LLLSDSGFYL ″+++″ 160 LLPPPSPAA ″+++″ 161 NLMLELETV ″+++″ 162 RLADLKVSI ″++++″ 163 SIFDAVLKGV ″++++″ 164 SLFDGAVISTV ″+++″ 165 KLLEEIEFL ″+++″ 167 SLFSITKSV ″+++″ 168 SLLSPLLSV ″+++″ 169 SSLEENLLHQV ″+++″ 171 TLLDVISAL ″++++″ 172 TLQDSLEFI ″++++″ 173 VILDSVASV ″++++″ 174 VLVEITDVDFAA ″++++″ 175 VMESILLRL ″+++″ 176 YLHIYESQL ″+++″ 177 YLYEAEEATTL ″+++″ 178 YVLQGEFFL ″+++″ 179 FVDTNLYFL ″+++″ 180 GILQLVESV ″+++″ 181 LLFDQNDKV ″+++″ 182 LLPPPPPVA ″++++″ 183 VLFETVLTI ″+++″ 184 AVLGTSWQL ″+++″ 185 FIAQLNNVEL ″+++″ 186 FLDVSRDFV ″++″ 187 FLNSFVFKM ″++″ 188 GLEDEMYEV ″++″ 189 SLSHLVPAL ″+++″ 190 GLIELVDQL ″+++″ 191 GLSDISAQV ″+++″ 192 GMAAEVPKV ″++″ 193 SLADSMPSL ″++″ 194 SLAPFDREPFTL ″++″ 195 ALIPDLNQI ″+++″ 197 YLLTDNVVKL ″++″ 198 GLLSAVSSV ″+++″ 199 SLNSTTWKV ″+++″ 200 YLLDFEDRL ″++++″ 201 YLNISQVNV ″+++″ 202 ALAAGGYDV ″++″ 203 ILDTIFHKV ″+++″ 204 RLCDIVVNV ″++″ 205 TLFYESPHL ″+++″ 206 SAVSGQWEV ″++″ 207 GLVGLLEQA ″++++″ 208 FLAVSLPLL ″+++″ 209 FLLDTISGL ″+++″ 210 FLAEQFEFL ″+++″ 211 FIDDLFAFV ″+++″ 212 FLIGQGAHV ″+++″ 213 YINEDEYEV ″++″ 214 FLFDGSMSL ″+++″ 215 QLFEEEIEL ″++″ 216 KVVSNLPAI ″++″ 217 AQFGAVLEV ″+++″ 218 ALDQFLEGI ″+++″ 219 ALLELENSV ″++″ 220 FLAEAPTAL ″++″ 221 FLAPDNSLLLA ″++++″ 222 FLIETGTLL ″+++″ 223 FLQDIPDGLFL ″++″ 224 FLSPLLPLL ″++″ 226 GVIDPVPEV ″++″ 227 IIAEGIPEA ″++″ 228 IIAEYLSYV ″++″ 229 ILSPWGAEV ″++++″ 230 IMDDDSYGV ″++″ 231 IVMGAIPSV ″+++″ 232 KVMEGTVAA ″++″ 233 MLEVHIPSV ″+++″ 234 NLQRTVVTV ″++″ 235 SLDVYELFL ″+++″ 236 SLFDGFFLTA ″++++″ 237 YLDRLIPQA ″+++″ 238 YQYGAVVTL ″+++″ 239 VLIDDTVLL ″+++″ 240 ALVPTPALFYL ″+++″ 241 FIPDFIPAV ″++″ 242 GILDFZVFL ″++++″ 243 GLPDLDIYL ″++++″ 244 ILEPFLPAV ″+++″ 245 KLIQLPVVYV ″+++″ 246 KLPVPLESV ″+++″ 247 KVLEMETTV ″+++″ 248 NLLEQFILL ″+++″ 249 VLLESLVEI ″++++″ 250 VLTNVGAAL ″+++″ 251 VLYELFTYI ″+++″ 252 YLGDLIMAL ″+++″ 253 YSDDDVPSV ″++++″ 254 FLYSETWNI ″++++″ 255 GMWNPNAPVFL ″++++″ 256 ALQETPPQV ″+++″ 257 FLQEWEVYA ″++++″ 258 RIYPFLLMV ″+++″ 259 TVLDGLEFKV ″++++″ 260 RLDEAFDFV ″++++″ 261 FLPETRIMTSV ″++++″ 262 LMGPVVHEV ″++++″ 263 GLMDNEIKV ″+++″ 264 ILTGTPPGV ″+++″ 265 ILWHFVASL ″++++″ 266 QLTEMLPSI ″++++″ 267 SLLETGSDLLL ″+++″ 268 VLFPLPTPL ″++++″ 269 VLQNVAFSV ″++++″ 270 VVVDSDSLAFV ″++++″ 271 YLLDQPVLEQRL ″++++″ 272 KLDHTLSQI ″+++″ 273 AILLPQPPK ″++″ 274 KLLNLISKL ″++++″ 275 KLMDLEDCAL ″++++″ 276 NMISYVVHL ″++″ 277 FLIDLNSTHGTFL ″+++″ 278 FLLFINHRL ″+++″ 279 NLAGENILNPL ″+++″ 280 SLLNHLPYL ″++++″ 281 TLQTVPLTTV ″++++″ 282 YLLEQGAQV ″++++″ 283 ALMPVTPQA ″+++″ 284 KLQEQIHRV ″+++″ 285 SITAVTPLL ″+++″ 286 HLTEDTPKV ″+++″ 287 ILMGHSLYM ″++++″ 288 RLAPEIVSA ″+++″ 289 SLLAANNLL ″++++″ 290 IASPVIAAV ″+++″ 291 KIIDTAGLSEA ″+++″ 292 KLINSQISL ″+++″ 293 GLAMVEAISYV ″++++″ 294 KLYGPEGLELV ″++++″ 295 SLAAVSQQL ″+++″ 296 FILEPLYKI ″++++″ 297 ILQNGLETL ″+++″ 298 ALTDVILCV ″++++″ 299 RLLEEEGVSL ″+++″ 300 IVLERNPEL ″+++″ 301 LQFDGIHVV ″+++″ 302 SLAELDEKISA ″+++″ 303 FVWEASHYL ″++++″ 304 ALIRLDDLFL ″+++″ 305 AMLAQQMQL ″+++″ 306 AQVALVNEV ″+++″ 307 FLLPVAVKL ″+++″ 308 SLLDQIPEM ″+++″ 309 SLSFVSPSL ″+++″ 310 VMAEAPPGV ″+++″ 311 YLHRQVAAV ″+++″ 314 LIDDKGTIKL ″++″

REFERENCE LIST

[0476] Aakula, A. et al., Eur. Urol. 69 (2016): 1120-1128 [0477] Aalto, Y. et al., Leukemia 15 (2001): 1721-1728 [0478] Abbruzzese, C. et al., J Exp. Clin Cancer Res 31 (2012): 4 [0479] Abraham, R. S. et al., Blood 105 (2005): 794-803 [0480] Adeola, H. A. et al., Oncotarget. 7 (2016): 13945-13964 [0481] Adinolfi, E. et al., J Osteoporos. 2012 (2012): 637863 [0482] Ahn, K. et al., Mol. Cells 28 (2009): 99-103 [0483] Akagi, T. et al., Int. J Cancer 125 (2009): 2349-2359 [0484] Al-Ahmadie, H. et al., Cancer Discov 4 (2014): 1014-1021 [0485] Alagaratnam, S. et al., Int. J Androl 34 (2011): e133-e150 [0486] Allison, J. P. et al., Science 270 (1995): 932-933 [0487] American Cancer Society, (2015), www.cancer.org [0488] Amos, C. I. et al., Hum. Mol. Genet. 20 (2011): 5012-5023 [0489] Andersen, R. S. et al., Nat. Protoc. 7 (2012): 891-902 [0490] Angele, S. et al., Br. J Cancer 91 (2004): 783-787 [0491] Antonopoulou, K. et al., J Invest Dermatol. 135 (2015): 1074-1079 [0492] Appay, V. et al., Eur. J Immunol. 36 (2006): 1805-1814 [0493] Arigoni, M. et al., Am. J Pathol. 182 (2013): 2058-2070 [0494] Aso, T. et al., Anticancer Res 35 (2015): 6819-6827 [0495] Atanackovic, D. et al., Am. J Hematol. 86 (2011): 918-922 [0496] Atienza, J. M. et al., Mol Cancer Ther 4 (2005): 361-368 [0497] Augustin, A. et al., Mol. Cancer Ther. 12 (2013): 520-529 [0498] Avirneni-Vadlamudi, U. et al., J Clin Invest 122 (2012): 403-407 [0499] Bae, J. S. et al., Am. J Pathol. (2016) [0500] Bae, J. S. et al., Int. J Cancer 136 (2015): 797-809 [0501] Banchereau, J. et al., Cell 106 (2001): 271-274 [0502] Bankovic, J. et al., Lung Cancer 67 (2010): 151-159 [0503] Baschieri, F. et al., Small GTPases. 6 (2015): 104-107 [0504] Baschieri, F. et al., Cell Cycle 14 (2015): 1139-1147 [0505] Bausch, D. et al., Clin Cancer Res. 17 (2011): 302-309 [0506] Beatty, G. et al., J Immunol 166 (2001): 2276-2282 [0507] Beggs, J. D., Nature 275 (1978): 104-109 [0508] Bekker-Jensen, S. et al., Nat Cell Biol 12 (2010): 80-86 [0509] Belle, L. et al., Sci. Signal. 8 (2015): ra18 [0510] Benevolo, M. et al., Am. J Surg. Pathol. 31 (2007): 76-84 [0511] Benjamini, Y. et al., Journal of the Royal Statistical Society. Series B (Methodological), Vol. 57 (1995): 289-300 [0512] Bertherat, J. et al., Cancer Res 63 (2003): 5308-5319 [0513] Bin, B. H. et al., PLoS. One. 10 (2015): e0129273 [0514] Boldrup, L. et al., Eur. J Cancer 48 (2012): 1401-1406 [0515] Bouameur, J. E. et al., J Invest Dermatol. 134 (2014): 885-894 [0516] Boulter, J. M. et al., Protein Eng 16 (2003): 707-711 [0517] Brandi, G. et al., Oncologist. 21 (2016): 600-607 [0518] Brastianos, P. K. et al., Nat Genet. 45 (2013): 285-289 [0519] Braumuller, H. et al., Nature (2013) [0520] Bravou, V. et al., Cancer Invest 33 (2015): 387-397 [0521] Briffa, R. et al., PLoS. One. 10 (2015): e0144708 [0522] Brossart, P. et al., Blood 90 (1997): 1594-1599 [0523] Bruckdorfer, T. et al., Curr. Pharm. Biotechnol. 5 (2004): 29-43 [0524] Bueno, R. C. et al., Ann. Oncol 25 (2014): 69-75 [0525] Busse-Wicher, M. et al., Matrix Biol 35 (2014): 25-33 [0526] Caccia, D. et al., J Proteome. Res 10 (2011): 4196-4207 [0527] Campos-Parra, A. D. et al., Gynecol. Oncol 143 (2016): 406-413 [0528] Cantu, C. et al., Blood 117 (2011): 3669-3679 [0529] Carbonnelle-Puscian, A. et al., Leukemia 23 (2009): 952-960 [0530] Card, K. F. et al., Cancer Immunol. Immunother. 53 (2004): 345-357 [0531] Cassard, L. et al., Int. J Cancer 123 (2008): 2832-2839 [0532] Cesaratto, L. et al., Cell Death. Dis. 7 (2016): e2374 [0533] Chang, S. H. et al., Mol. Ther. 20 (2012): 2052-2063 [0534] Chanock, S. J. et al., Hum. Immunol. 65 (2004): 1211-1223 [0535] Chatterjee, N. et al., Cancer Biol Ther. 14 (2013): 658-671 [0536] Chen, H. et al., Proteomics. 14 (2014a): 51-73 [0537] Chen, J. et al., Gut Liver (2016) [0538] Chen, J. H. et al., Int. J Biol Macromol. 81 (2015a): 615-623 [0539] Chen, K. et al., Nat Commun. 5 (2014b): 4682 [0540] Chen, R. et al., J Int. Med. Res 39 (2011): 533-540 [0541] Chen, S. et al., Int. J Oncol. 45 (2014c): 448-458 [0542] Chen, S. T. et al., Hum. Pathol. 39 (2008): 1854-1858 [0543] Chen, W. T. et al., Elife. 4 (2015b) [0544] Chen, Y. et al., J Biol Chem 287 (2012): 24082-24091 [0545] Chiriva-Internati, M. et al., J Immunother. 34 (2011): 490-499 [0546] Chung, G. T. et al., J Pathol. 231 (2013): 158-167 [0547] Chung, K. Y. et al., Hepatology 54 (2011): 307-318 [0548] Chung, P. Y. et al., Semin. Arthritis Rheum. 41 (2012): 619-641 [0549] Cohen, C. J. et al., J Mol. Recognit. 16 (2003a): 324-332 [0550] Cohen, C. J. et al., J Immunol. 170 (2003b): 4349-4361 [0551] Cohen, S. N. et al., Proc. Natl. Acad. Sci. U.S.A 69 (1972): 2110-2114 [0552] Coligan, J. E. et al., Current Protocols in Protein Science (1995) [0553] Colombetti, S. et al., J Immunol. 176 (2006): 2730-2738 [0554] Conesa-Zamora, P. et al., Clin Epigenetics. 7 (2015): 101 [0555] Coyaud, E. et al., Blood 115 (2010): 3089-3097 [0556] Cubillos-Rojas, M. et al., J Biol Chem 289 (2014): 14782-14795 [0557] Cuppini, L. et al., PLoS. One. 8 (2013): e74345 [0558] Dai, X. et al., Breast Cancer Res Treat. 149 (2015): 363-371 [0559] Daulat, A. M. et al., Dev. Cell 37 (2016): 311-325 [0560] Davidson, B. et al., Gynecol. Oncol 128 (2013): 364-370 [0561] Dawlaty, M. M. et al., Cell 133 (2008): 103-115 [0562] De, Marchi E. et al., Adv. Protein Chem Struct. Biol 104 (2016): 39-79 [0563] Deb, S. et al., Br. J Cancer 110 (2014): 1606-1613 [0564] Dengjel, J. et al., Clin Cancer Res 12 (2006): 4163-4170 [0565] Denkberg, G. et al., J Immunol. 171 (2003): 2197-2207 [0566] DeRycke, M. S. et al., Am. J Clin Pathol. 132 (2009): 846-856 [0567] Devaney, J. M. et al., Prostate Cancer Prostatic. Dis. (2013) [0568] Devaney, J. M. et al., Epigenetics. 10 (2015): 319-328 [0569] Dong, F. et al., Pathol. Oncol Res 21 (2015a): 1273-1275 [0570] Dong, F. et al., Diagn. Pathol. 10 (2015b): 137 [0571] Dong, Y. et al., Mol. Cancer Ther. 4 (2005): 1047-1055 [0572] Doubrovina, E. S. et al., J Immunol. 171 (2003): 6891-6899 [0573] Drake, P. M. et al., J Proteome. Res 11 (2012): 2508-2520 [0574] Driscoll, D. R. et al., Cancer Res 76 (2016): 6911-6923 [0575] Dube, N. et al., Cell Signal. 20 (2008): 1608-1615 [0576] Dun, B. et al., Am. J Transl. Res 6 (2013a): 28-42 [0577] Dun, B. et al., Int. J Clin Exp. Pathol. 6 (2013b): 2880-2886 [0578] Dunn, L. L. et al., Carcinogenesis 27 (2006): 2157-2169 [0579] Dunwell, T. L. et al., Epigenetics. 4 (2009): 185-193 [0580] Dus-Szachniewicz, K. et al., Anticancer Res 35 (2015): 6551-6561 [0581] Emori, M. et al., PLoS. One. 8 (2013): e84187 [0582] Emori, M. et al., J Surg. Oncol 111 (2015): 975-979 [0583] Engel, B. E. et al., Cell Death. Dis. 4 (2013): e938 [0584] Erbe, A. K. et al., Clin Cancer Res (2016) [0585] Fachal, L. et al., Nat Genet. 46 (2014): 891-894 [0586] Falk, K. et al., Nature 351 (1991): 290-296 [0587] Feijs, K. L. et al., Nat Rev Mol. Cell Biol 14 (2013): 443-451 [0588] Ferlay et al., GLOBOCAN 2012 v 1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet], (2013), globocan.iarc.fr [0589] Fernandez, M. et al., Methods Mol. Biol 854 (2012): 239-252 [0590] Fernandez-Perez, M. P. et al., Neoplasia. 15 (2013): 826-839 [0591] Ferrero, S. et al., Histol. Histopathol. 30 (2015): 473-478 [0592] Feuerborn, A. et al., Oncogene 34 (2015): 1185-1195 [0593] Follenzi, A. et al., Nat Genet. 25 (2000): 217-222 [0594] Fong, L. et al., Proc. Natl. Acad. Sci. U.S.A 98 (2001): 8809-8814 [0595] Fouz, N. et al., Appl. Biochem. Biotechnol. 173 (2014): 1618-1639 [0596] Fu, W. et al., BMC. Cancer 9 (2009): 114 [0597] Fu, W. et al., Cell Rep. 17 (2016): 1505-1517 [0598] Fujimoto, A. et al., Nat Genet. 48 (2016): 500-509 [0599] Fujita, M. et al., J Biol Chem 282 (2007): 5736-5748 [0600] Fujitomo, T. et al., Cancer Res 72 (2012): 4110-4118 [0601] Gabrilovich, D. I. et al., Nat. Med 2 (1996): 1096-1103 [0602] Galland, F. et al., Endocr. Relat Cancer 17 (2010): 361-371 [0603] Gallou, C. et al., Oncotarget. (2016) [0604] Gao, F. et al., Biochem. Biophys. Res Commun. 431 (2013): 610-616 [0605] Gao, J. et al., Dis. Markers 24 (2008): 127-134 [0606] Gasser, J. A. et al., Mol. Cell 56 (2014): 595-607 [0607] Gattinoni, L. et al., Nat. Rev. Immunol. 6 (2006): 383-393 [0608] Geoffroy-Perez, B. et al., Int. J Cancer 93 (2001): 288-293 [0609] Ghalali, A. et al., Carcinogenesis 35 (2014): 1547-1555 [0610] Giebel, S. et al., Hum. Immunol. 75 (2014): 508-513 [0611] Gillis, L. D. et al., Oncogene 32 (2013): 3598-3605 [0612] Gnjatic, S. et al., Proc Natl. Acad. Sci. U.S.A 100 (2003): 8862-8867 [0613] Godkin, A. et al., Int. Immunol 9 (1997): 905-911 [0614] Goodison, S. et al., BMC. Genomics 4 (2003): 39 [0615] Gorodeski, G. I., Expert. Opin. Ther. Targets. 13 (2009): 1313-1332 [0616] Gotoh, M. et al., Genes Chromosomes. Cancer 53 (2014): 1018-1032 [0617] Grant, R. C. et al., Hum. Genomics 7 (2013): 11 [0618] Green, M. R. et al., Molecular Cloning, A Laboratory Manual 4th (2012) [0619] Greenfield, E. A., Antibodies: A Laboratory Manual 2nd (2014) [0620] Grzmil, M. et al., Oncogene 29 (2010): 4080-4089 [0621] Guerreiro, A. S. et al., Mol. Cancer Res 9 (2011): 925-935 [0622] Guo, S. T. et al., Oncogene (2015) [0623] Guo, X. et al., Cancer Epidemiol. 37 (2013): 732-736 [0624] Gustafsson, C. et al., Trends Biotechnol. 22 (2004): 346-353 [0625] Hagmann, W. et al., Neoplasia. 12 (2010): 740-747 [0626] Hao, J. et al., Oncotarget. 6 (2015): 42028-42039 [0627] Harato, M. et al., BMC. Neurosci. 13 (2012): 149 [0628] Hasumi, H. et al., Int. J Urol. 23 (2016): 204-210 [0629] Hasumi, H. et al., Proc. Natl. Acad. Sci. U.S.A 112 (2015): E1624-E1631 [0630] Haun, R. S. et al., J Proteomics. Bioinform. Suppl 10 (2014): 510003 [0631] He, H. et al., J Clin Endocrinol. Metab 98 (2013): E973-E980 [0632] Heinonen, H. et al., Int. J Cancer 137 (2015): 2374-2383 [0633] Hertzman, Johansson C. et al., Melanoma Res 23 (2013): 360-365 [0634] Heul-Nieuwenhuijsen, L. et al., BJU. Int. 103 (2009): 1574-1580 [0635] Hibbs, K. et al., Am. J Pathol. 165 (2004): 397-414 [0636] Hinrichs, C. S. et al., Nat Biotechnol. 31 (2013): 999-1008 [0637] Ho, C. Y. et al., Neuro. Oncol 15 (2013): 69-82 [0638] Hoover, H. et al., J Proteome. Res 14 (2015): 3670-3679 [0639] Hope, E. R. et al., Gynecol. Oncol 140 (2016): 503-511 [0640] Hou, M. et al., Oncol Lett. 10 (2015): 23-26 [0641] Hu, N. et al., Cancer Res 76 (2016): 1714-1723 [0642] Huang, A. H. et al., PLoS. One. 10 (2015): e0118530 [0643] Huang, J. M. et al., Oncogene 32 (2013): 2220-2229 [0644] Huang, L. et al., PLoS. One. 9 (2014a): e98185 [0645] Huang, L. et al., PLoS. One. 9 (2014b): e86336 [0646] Huang, X. et al., APMIS 122 (2014c): 1070-1079 [0647] Huynh, K. M. et al., Gene 433 (2009): 32-39 [0648] Hwang, M. L. et al., J Immunol. 179 (2007): 5829-5838 [0649] Ilboudo, A. et al., BMC. Cancer 14 (2014): 7 [0650] Ishiguro, H. et al., Oncogene 21 (2002): 6387-6394 [0651] Ishikawa, S. et al., J Exp. Clin Cancer Res. 22 (2003): 299-306 [0652] Ishiwata, T. et al., World J Gastroenterol. 17 (2011): 409-418 [0653] Isikbay, M. et al., Horm. Cancer 5 (2014): 72-89 [0654] Ito, M. et al., Breast Cancer Res Treat. 144 (2014): 59-69 [0655] Ito, Y. et al., Oncology 71 (2006): 388-393 [0656] Ivanov, S. V. et al., Br. J Cancer 109 (2013): 444-451 [0657] Januchowski, R. et al., Oncol Rep. 32 (2014): 1981-1990 [0658] Jia, W. et al., Oncotarget. (2016) [0659] Jiang, L. et al., Hum. Genet. 129 (2011): 189-197 [0660] Jiang, W. et al., Tumour. Biol 36 (2015): 1289-1297 [0661] Jiao, S. et al., Cancer Cell 25 (2014): 166-180 [0662] Jin, Y. et al., PLoS. One. 10 (2015): e0144187 [0663] Jing, J. et al., Mol. Med Rep. 11 (2015): 3337-3343 [0664] Joel, M. et al., Mol. Cancer 14 (2015): 121 [0665] Jones, D. T. et al., Oncogene 28 (2009): 2119-2123 [0666] Jung, G. et al., Proc Natl Acad Sci USA 84 (1987): 4611-4615 [0667] Junnila, S. et al., BMC. Cancer 10 (2010): 73 [0668] Kang, M. R. et al., J Pathol. 217 (2009): 702-706 [0669] Kang, R. et al., Sci. Rep. 6 (2016): 19930 [0670] Karhemo, P. R. et al., J Proteomics. 77 (2012): 87-100 [0671] Karlsson, J. et al., Genes Chromosomes. Cancer 53 (2014): 381-391 [0672] Katada, K. et al., J Proteomics. 75 (2012): 1803-1815 [0673] Kataoka, K. et al., Nat Genet. 47 (2015): 1304-1315 [0674] Kato, N. et al., Int. J Cancer 41 (1988): 380-385 [0675] Kaufman, H. L. et al., Nat Rev Clin Oncol 10 (2013): 588-598 [0676] Kibbe, A. H., Handbook of Pharmaceutical Excipients rd (2000) [0677] Killian, A. et al., Genes Chromosomes. Cancer 45 (2006): 874-881 [0678] Kim H R et al., J Clin Oncol 34, 2016 (suppl; abstr 6055) (2016) [0679] Kim, J. et al., Genes Chromosomes. Cancer 54 (2015a): 681-691 [0680] Kim, O. et al., Mol. Med Rep. 12 (2015b): 2161-2168 [0681] Kim, S. Y. et al., Biochem. Biophys. Res Commun. 429 (2012): 173-179 [0682] Kimura, Y. et al., J Cancer 7 (2016): 702-710 [0683] Koo, S. et al., Anticancer Res 35 (2015): 3209-3215 [0684] Korshunov, A. et al., Am. J Pathol. 163 (2003): 1721-1727 [0685] Kousted, T. M. et al., Thromb. Haemost. 111 (2014): 29-40 [0686] Kren, B. T. et al., Breast Cancer Res 17 (2015): 19 [0687] Krieg, A. M., Nat. Rev. Drug Discov. 5 (2006): 471-484 [0688] Kuball, J. et al., Blood 109 (2007): 2331-2338 [0689] Kunicka, T. et al., BMC. Cancer 16 (2016): 795 [0690] Laczmanska, I. et al., Acta Biochim. Pol. 58 (2011): 467-470 [0691] Lahoz, A. et al., Oncogene 32 (2013): 4854-4860 [0692] Lajmi, N. et al., Br. J Haematol. 171 (2015): 752-762 [0693] Lan, L. et al., Int. J Cancer 126 (2010): 53-64 [0694] Lang, F. et al., Int. J Biochem. Cell Biol 42 (2010): 1571-1575 [0695] Lee, K. Y. et al., J Med. 35 (2004): 141-149 [0696] Lee, M. H. et al., J Korean Neurosurg. Soc. 43 (2008): 190-193 [0697] Lee, S. E. et al., Hematol. Oncol 32 (2014): 221-224 [0698] Lee, S. H. et al., Pathol. Oncol Res 21 (2015): 847-848 [0699] Lee, Y. H. et al., Food Chem 141 (2013): 381-388 [0700] Li, C. et al., PLoS. Biol 14 (2016a): e1002416 [0701] Li, F. et al., FEBS J 279 (2012a): 1261-1273 [0702] Li, F. et al., Gene 503 (2012b): 200-207 [0703] Li, G. et al., Histopathology 50 (2007): 642-647 [0704] Li, H. et al., Virchows Arch. 466 (2015a): 581-588 [0705] Li, H. et al., Med Oncol 32 (2015b): 83 [0706] Li, N. et al., Am. J Cancer Res 5 (2015c): 1158-1168 [0707] Li, W. et al., J Gastroenterol. Hepatol. 30 (2015d): 1085-1093 [0708] Li, W. H. et al., Dis. Markers 2015 (2015e): 657570 [0709] Li, Y. et al., Oncotarget. (2016b) [0710] Liang, J. et al., Biochem. Cell Biol 85 (2007): 375-383 [0711] Liddy, N. et al., Nat. Med. 18 (2012): 980-987 [0712] Lim, J. H., BMB. Rep. 47 (2014): 405-410 [0713] Lim, J. H. et al., Cancer Genet. 207 (2014): 40-45 [0714] Lin, J. I. et al., Sci. Signal. 6 (2013): e4 [0715] Lind, G. E. et al., Mol. Cancer 10 (2011): 85 [0716] Linehan, W. M. et al., Nat Rev Urol. 7 (2010): 277-285 [0717] Linkous, A. et al., Clin Cancer Res 15 (2009): 1635-1644 [0718] Lips, E. H. et al., BMC. Cancer 8 (2008): 314 [0719] Lisitskaia, K. V. et al., Mol. Gen. Mikrobiol. Virusol. (2010): 34-37 [0720] Liu, H. et al., Tumour. Biol 36 (2015a): 5039-5049 [0721] Liu, H. et al., Anticancer Drugs 26 (2015b): 667-677 [0722] Liu, M. et al., Hepatology 55 (2012): 1754-1765 [0723] Liu, X. et al., Oncogene 32 (2013): 1266-1273 [0724] Ljunggren, H. G. et al., J Exp. Med 162 (1985): 1745-1759 [0725] Longenecker, B. M. et al., Ann N.Y. Acad. Sci. 690 (1993): 276-291 [0726] Lonsdale, J., Nat. Genet. 45 (2013): 580-585 [0727] Lukas, T. J. et al., Proc. Natl. Acad. Sci. U.S.A 78 (1981): 2791-2795 [0728] Lundblad, R. L., Chemical Reagents for Protein Modification 3rd (2004) [0729] Luo, J. et al., Tumour. Biol 37 (2016): 10715-10721 [0730] Ma, J. et al., Mol. Med Rep. 12 (2015): 6060-6064 [0731] Maesako, Y. et al., Int. J Hematol. 99 (2014): 202-207 [0732] Man, X. Y. et al., Arthritis Res Ther. 14 (2012): R144 [0733] Manceau, G. et al., Int. J Cancer 132 (2013): 2217-2221 [0734] Mancuso, P. et al., PLoS. One. 9 (2014): e114713 [0735] Marchetti, A. et al., Int. J Oncol 18 (2001): 175-179 [0736] Marchi, S. et al., Cell Death. Dis. 3 (2012): e304 [0737] Markus, M. A. et al., Genomics 107 (2016): 138-144 [0738] Mathysen, D. et al., Eur. J Cancer 40 (2004): 1255-1261 [0739] Matsuda, Y. et al., Pancreas 45 (2016): 93-100 [0740] Matsuo, Y. et al., PLoS. One. 5 (2010): e10481 [0741] Matsuo, Y. et al., Sci. Transl. Med. 6 (2014): 259ra145 [0742] McKee, C. M. et al., Oncotarget. 6 (2015): 3784-3796 [0743] McKee, C. M. et al., Oncotarget. 4 (2013): 1-2 [0744] McKiernan, E. et al., Tumour. Biol 32 (2011): 441-450 [0745] McSherry, E. A. et al., Breast Cancer Res 13 (2011): R31 [0746] Melhem, A. et al., Clin Cancer Res 15 (2009): 3196-3204 [0747] Mendez, E. et al., Clin Cancer Res 17 (2011): 2466-2473 [0748] Mertens-Walker, I. et al., BMC. Cancer 15 (2015): 164 [0749] Meszaros, B. et al., Biol Direct. 11 (2016): 23 [0750] Meziere, C. et al., J Immunol 159 (1997): 3230-3237 [0751] Miyoshi, T. et al., Clin Cancer Res (2016) [0752] Mochmann, L. H. et al., Oncotarget. 5 (2014): 351-362 [0753] Mohseni, M. et al., Proc. Natl. Acad. Sci. U.S.A 111 (2014): 17606-17611 [0754] Moon, J. W. et al., J Exp. Clin Cancer Res. 33 (2014): 4 [0755] Moretti, D. et al., PLoS. One. 10 (2015): e0117258 [0756] Morgan, R. A. et al., Science 314 (2006): 126-129 [0757] Mori, M. et al., Transplantation 64 (1997): 1017-1027 [0758] Morotti, A. et al., Cell Cycle 14 (2015): 973-979 [0759] Morowitz, M. J. et al., Clin Cancer Res 11 (2005): 2680-2685 [0760] Morris, M. R. et al., Oncogene 29 (2010): 2104-2117 [0761] Morrison, Joly M. et al., Cancer Res 76 (2016): 4752-4764 [0762] Mortara, L. et al., Clin Cancer Res. 12 (2006): 3435-3443 [0763] Mound, A. et al., Eur. J Cancer 49 (2013): 3738-3751 [0764] Mueller, L. N. et al., J Proteome. Res. 7 (2008): 51-61 [0765] Mueller, L. N. et al., Proteomics. 7 (2007): 3470-3480 [0766] Mughal, A. A. et al., Mol. Cancer 14 (2015): 160 [0767] Mumberg, D. et al., Proc. Natl. Acad. Sci. U.S.A 96 (1999): 8633-8638 [0768] Munkacsy, G. et al., Br. J Cancer 102 (2010): 361-368 [0769] Murrin, L. C. et al., J Neuroimmune. Pharmacol. 2 (2007): 290-295 [0770] Musolino, A. et al., J Clin Oncol 26 (2008): 1789-1796 [0771] Nagahara, A. et al., Biochem. Biophys. Res Commun. 391 (2010): 1641-1646 [0772] Nagel, S. et al., Genes Chromosomes. Cancer 53 (2014): 917-933 [0773] Nakayama, S. et al., Anticancer Res 35 (2015): 261-268 [0774] Nan, H. et al., Int. J Cancer 125 (2009): 909-917 [0775] National Cancer Institute, (5-6-2015), www.cancer.gov [0776] Navarro, M. S. et al., Cancer Cell 13 (2008): 293-295 [0777] Ng, L. et al., Hepatology 58 (2013): 667-679 [0778] Ni, R. S. et al., Oncol Lett. 4 (2012): 1354-1360 [0779] Nord, H. et al., Neuro. Oncol 11 (2009): 803-818 [0780] Nordh, S. et al., World J Gastroenterol. 20 (2014): 8482-8490 [0781] Nordlund, J. et al., PLoS. ONE. 7 (2012): e34513 [0782] North, S. et al., J Urol. 191 (2014): 35-39 [0783] Norton, N. et al., Cancer Immunol. Res 2 (2014): 962-969 [0784] Oh, Y. et al., J Biol. Chem 287 (2012): 17517-17529 [0785] Olstad, O. K. et al., Anticancer Res 23 (2003): 2201-2216 [0786] Orr, B. et al., Oncogene 31 (2012): 1130-1142 [0787] Osterstrom, A. et al., Cancer Lett. 182 (2002): 175-182 [0788] Ozbay, P. O. et al., Onco. Targets. Ther. 6 (2013): 621-627 [0789] Pangeni, R. P. et al., Clin Epigenetics. 7 (2015): 57 [0790] Parhamifar, L. et al., Carcinogenesis 26 (2005): 1988-1998 [0791] Park, H. et al., Proc. Natl. Acad. Sci. U.S.A 111 (2014): 7066-7071 [0792] Parris, T. Z. et al., Clin Cancer Res 16 (2010): 3860-3874 [0793] Patai, A. V. et al., PLoS. One. 10 (2015): e0133836 [0794] Pei, X. H. et al., Biochem. Biophys. Res. Commun. 446 (2014): 322-327 [0795] Pei, Z. et al., PLoS. One. 8 (2013): e69392 [0796] Pelzl, L. et al., Cell Physiol Biochem. 37 (2015): 1857-1868 [0797] Peng, Y. et al., Cancer Res 75 (2015): 378-386 [0798] Perdigao, P. F. et al., Genes Chromosomes. Cancer 44 (2005): 204-211 [0799] Pereira, J. S. et al., Endocrine. 49 (2015): 204-214 [0800] Pestov, D. G. et al., Mol. Cell Biol 21 (2001): 4246-4255 [0801] Peters, D. G. et al., Cancer Epidemiol. Biomarkers Prev. 14 (2005): 1717-1723 [0802] Petit, C. S. et al., J Cell Biol 202 (2013): 1107-1122 [0803] Petricevic, B. et al., J Transl. Med 11 (2013): 307 [0804] Phan, G. Q. et al., Cancer Control 20 (2013): 289-297 [0805] Pho, L. N. et al., G. Ital. Dermatol. Venereol. 145 (2010): 37-45 [0806] Piepoli, A. et al., Exp. Biol Med. (Maywood.) 237 (2012): 1123-1128 [0807] Pignatelli, J. et al., J Biol Chem 287 (2012): 37309-37320 [0808] Pinheiro, J. et al., nlme: Linear and Nonlinear Mixed Effects Models (CRAN.R-project.org/packe=nlme) (2015) [0809] Plebanski, M. et al., Eur. J Immunol 25 (1995): 1783-1787 [0810] Polevoda, B. et al., Biochem. Biophys. Res Commun. 308 (2003): 1-11 [0811] Porkka, K. P. et al., Genes Chromosomes. Cancer 39 (2004): 1-10 [0812] Porta, C. et al., Virology 202 (1994): 949-955 [0813] Powell, A. G. et al., J Cancer Res Clin Oncol 138 (2012): 723-728 [0814] Prasad, V. et al., J Virol. 88 (2014): 13086-13098 [0815] Qi, J. et al., Gut (2015) [0816] Qin, J. et al., Cell Physiol Biochem. 35 (2015): 2069-2077 [0817] Qin, X. Y. et al., FEBS Lett. 585 (2011a): 3310-3315 [0818] Qin, Y. R. et al., Clin Cancer Res 17 (2011b): 46-55 [0819] Rabjerg, M. et al., APMIS 124 (2016): 372-383 [0820] Rajaram, M. et al., PLoS. One. 8 (2013): e66264 [0821] Rajkumar, T. et al., Asian Pac. J Cancer Prev. 16 (2015): 5211-5217 [0822] Rammensee, H. G. et al., Immunogenetics 50 (1999): 213-219 [0823] Rankin, C. T. et al., Blood 108 (2006): 2384-2391 [0824] Raymond, J. R., Jr. et al., J Ovarian. Res 7 (2014): 6 [0825] RefSeq, The NCBI handbook [Internet], Chapter 18, (2002), www.ncbi.nlm.nih.gov/books/NBK21091 [0826] Rho, J. H. et al., J Proteome. Res 7 (2008): 2959-2972 [0827] Rhyu, D. W. et al., Int. J Mol. Sci. 15 (2014): 9173-9183 [0828] Ricketts, C. J. et al., PLoS. ONE. 9 (2014): e85621 [0829] Rini, B. I. et al., Cancer 107 (2006): 67-74 [0830] Roberts, N. J. et al., Cancer Discov 2 (2012): 41-46 [0831] Rock, K. L. et al., Science 249 (1990): 918-921 [0832] Rodenko, B. et al., Nat. Protoc. 1 (2006): 1120-1132 [0833] Roger, S. et al., Biochim. Biophys. Acta 1848 (2015): 2584-2602 [0834] Rohrmoser, M. et al., Mol. Cell Biol 27 (2007): 3682-3694 [0835] Romagne, F. et al., Blood 114 (2009): 2667-2677 [0836] Rondeau, S. et al., Br. J Cancer 112 (2015): 1059-1066 [0837] Rouette, A. et al., Sci. Rep. 6 (2016): 34019 [0838] Ruffini, F. et al., Oncol Rep. 30 (2013): 2887-2896 [0839] Ruiz, J. F. et al., Nucleic Acids Res 32 (2004): 5861-5873 [0840] Russell, R. et al., Nat Commun. 6 (2015): 7677 [0841] S3-Leitlinie Melanom, 032-0240L, (2013) [0842] Saiki, R. K. et al., Science 239 (1988): 487-491 [0843] Sakakura, C. et al., Anticancer Res 23 (2003): 3691-3697 [0844] Sakakura, H. et al., PLoS. One. 9 (2014): e83385 [0845] Sakashita, K. et al., Oncol Rep. 20 (2008): 1313-1319 [0846] Sakre, N. et al., Oncotarget. (2016) [0847] Sanders, S. et al., Cytogenet. Cell Genet. 88 (2000): 324-325 [0848] Santarlasci, V. et al., Eur. J Immunol. 44 (2014): 654-661 [0849] Sarver, A. E. et al., Lab Invest 95 (2015): 1077-1088 [0850] Schmidt, L. S. et al., Expert. Opin. Orphan. Drugs 3 (2015a): 15-29 [0851] Schmidt, L. S. et al., Nat Rev Urol. 12 (2015b): 558-569 [0852] Schmitt, T. M. et al., Hum. Gene Ther. 20 (2009): 1240-1248 [0853] Scholten, K. B. et al., Clin Immunol. 119 (2006): 135-145 [0854] Schramm, A. et al., Nat Genet. 47 (2015): 872-877 [0855] Schwirzke, M. et al., Anticancer Res 18 (1998): 1409-1421 [0856] Scortegagna, M. et al., Cancer Res 75 (2015): 1399-1412 [0857] Seeger, F. H. et al., Immunogenetics 49 (1999): 571-576 [0858] Selvakumar, P. et al., Mol. Cancer 8 (2009): 65 [0859] Semczuk, A. et al., Pathol. Res Pract. 209 (2013): 740-744 [0860] Sesen, J. et al., Int. J Mol. Sci. 15 (2014): 2172-2190 [0861] Seydi, E. et al., Hepat. Mon. 15 (2015): e33073 [0862] Shah, P. et al., J Biol Chem 288 (2013): 12345-12352 [0863] Sherman, F. et al., Laboratory Course Manual for Methods in Yeast Genetics (1986) [0864] Shi, J. et al., Yonsei Med J 57 (2016): 549-556 [0865] Shi, J. L. et al., Oncotarget. 6 (2015a): 5299-5309 [0866] Shi, X. et al., Oncol Lett. 10 (2015b): 1309-1314 [0867] Shi, Y. et al., Prostaglandins Leukot. Essent. Fatty Acids 74 (2006): 309-315 [0868] Shibao, K. et al., Cell Calcium 48 (2010): 315-323 [0869] Shimakata, T. et al., Histopathology (2016) [0870] Shimizu, H. et al., Adv. Clin Exp. Med 25 (2016): 117-128 [0871] Shimozono, N. et al., Cancer Res 75 (2015): 4458-4465 [0872] Shin, J. et al., J Proteome. Res 13 (2014): 4919-4931 [0873] Shodeinde, A. et al., J Mol Biochem. 2 (2013): 18-26 [0874] Singh-Jasuja, H. et al., Cancer Immunol. Immunother. 53 (2004): 187-195 [0875] Small, E. J. et al., J Clin Oncol. 24 (2006): 3089-3094 [0876] Smirnova, T. et al., Oncotarget. (2016) [0877] Smith, L. M. et al., Mol. Cancer Ther. 5 (2006): 1474-1482 [0878] Sousa, S. F. et al., Endocr. Relat Cancer 22 (2015): 399-408 [0879] Srivastava, N. et al., Cancer Manag. Res. 6 (2014): 279-289 [0880] Stacey, S. N. et al., Nat Genet. 41 (2009): 909-914 [0881] Steen, H. C. et al., J Interferon Cytokine Res. 32 (2012): 103-110 [0882] Stetler, D. A. et al., Proc. Natl. Acad. Sci. U.S.A 78 (1981): 7732-7736 [0883] Sticz, T. et al., J Clin Pathol. (2016) [0884] Strissel, P. L. et al., Oncotarget. 3 (2012): 1204-1219 [0885] Sturm, M. et al., BMC. Bioinformatics. 9 (2008): 163 [0886] Su, H. T. et al., Mol. Cancer Res 11 (2013): 768-779 [0887] Suh, J. H. et al., Oncologist. 21 (2016): 684-691 [0888] Sumantran, V. N. et al., Indian J Biochem. Biophys. 52 (2015): 125-131 [0889] Supernat, A. et al., Oncol Lett. 4 (2012): 727-732 [0890] Suryo, Rahmanto Y. et al., Biochim. Biophys. Acta 1820 (2012): 237-243 [0891] Swift, M. et al., N. Engl. J Med. 316 (1987): 1289-1294 [0892] Tada, M. et al., Cancer Sci. 101 (2010): 1261-1269 [0893] Talarico, C. et al., Oncotarget. 6 (2015): 37511-37525 [0894] Tan, Y. et al., Curr. Pharm. Des 20 (2014): 81-87 [0895] Tanic, N. et al., Anticancer Res. 26 (2006): 2137-2142 [0896] Tao, J. et al., Tumour. Biol 35 (2014): 12083-12090 [0897] Telikicherla, D. et al., J Proteomics. Bioinform. 5 (2012): 122-126 [0898] Teufel, R. et al., Cell Mol. Life Sci. 62 (2005): 1755-1762 [0899] Thomsen, H. et al., BMC. Cancer 16 (2016): 227 [0900] Tokheim, C. et al., Cancer Res 76 (2016): 3719-3731 [0901] Tong, W. G. et al., Epigenetics. 5 (2010): 499-508 [0902] Tran, E. et al., Science 344 (2014): 641-645 [0903] Trivedi, S. et al., Clin Cancer Res 22 (2016): 5229-5237 [0904] Tsai, C. H. et al., Mol. Med Rep. 12 (2015): 7326-7334 [0905] Tschaharganeh, D. F. et al., Cell 158 (2014): 579-592 [0906] Tsun, Z. Y. et al., Mol. Cell 52 (2013): 495-505 [0907] Tyszkiewicz, T. et al., Folia Histochem. Cytobiol. 52 (2014): 79-89 [0908] Ueda, R. et al., Int. J Cancer 120 (2007): 1704-1711 [0909] van den Broek, E. et al., PLoS. One. 10 (2015): e0138141 [0910] Vasseur, S. et al., Mol. Cancer 4 (2005): 4 [0911] Velikkakath, A. K. et al., Mol. Biol. Cell 23 (2012): 896-909 [0912] Visuttijai, K. et al., PLoS. One. 11 (2016): e0164063 [0913] Vogler, M. et al., Cell Death. Differ. 15 (2008): 820-830 [0914] Wagenblast, E. et al., Nature 520 (2015): 358-362 [0915] Walter, S. et al., J. Immunol. 171 (2003): 4974-4978 [0916] Walter, S. et al., Nat Med. 18 (2012): 1254-1261 [0917] Wang, C. J. et al., Tumour. Biol 34 (2013a): 2141-2146 [0918] Wang, D. et al., Med. Oncol 32 (2015a): 461 [0919] Wang, J. et al., J Clin Invest 112 (2003): 535-543 [0920] Wang, J. et al., Cancer Prev. Res (Phila) 6 (2013b): 321-330 [0921] Wang, K. et al., J Cancer Res Clin Oncol 141 (2015b): 805-812 [0922] Wang, L. et al., Xi. Bao. Yu Fen. Zi. Mian. Yi. Xue. Za Zhi. 31 (2015c): 1251-1254 [0923] Wang, L. F. et al., Nan. Fang Yi. Ke. Da. Xue. Xue. Bao. 36 (2016a): 396-400 [0924] Wang, L. H. et al., Biochim. Biophys. Acta 1823 (2012): 505-513 [0925] Wang, L. J. et al., Oncotarget. 6 (2015d): 5932-5946 [0926] Wang, S. et al., Pharmacogenomics. 17 (2016b): 1637-1647 [0927] Wang, X. et al., Neuron 36 (2002): 843-854 [0928] Wang, Y. et al., Mol. Endocrinol. 28 (2014): 935-948 [0929] Wang, Z. et al., Science 304 (2004): 1164-1166 [0930] Wang, Z. et al., Melanoma Res 14 (2004): 107-114 [0931] Weber, A. M. et al., Pharmacol. Ther (2014) [0932] Weigman, V. J. et al., Breast Cancer Res Treat. 133 (2012): 865-880 [0933] Welinder, C. et al., J Proteome. Res 13 (2014a): 1315-1326 [0934] Welinder, C. et al., PLoS. One. 9 (2014b): e110804 [0935] Weng, W. K. et al., Leuk. Lymphoma 50 (2009): 1494-1500 [0936] Westcot, S. E. et al., PLoS. One. 10 (2015): e0130688 [0937] Willcox, B. E. et al., Protein Sci. 8 (1999): 2418-2423 [0938] Wills, M. K. et al., Biochem. J 447 (2012): 1-16 [0939] Wills, M. K. et al., Mol. Biol Cell 25 (2014): 739-752 [0940] Wisniewski, A. et al., Hum. Immunol. 73 (2012): 927-931 [0941] World Cancer Report, (2014) [0942] Wrzeszczynski, K. O. et al., PLoS. ONE. 6 (2011): e28503 [0943] Wu, X. et al., Hum. Mol. Genet. 21 (2012): 456-462 [0944] Wu, Y. et al., Int. J Mol. Sci. 17 (2016) [0945] Wyatt, L. et al., Cell Cycle 7 (2008): 2290-2295 [0946] Xiao, F. et al., Hum. Genet. 133 (2014): 559-574 [0947] Xie, X. et al., Mol. Cell Biochem. 301 (2007): 115-122 [0948] Xing, X. et al., Gene 344 (2005): 161-169 [0949] Xu, G. et al., Gastroenterol. Res Pract. 2016 (2016a): 8431480 [0950] Xu, H. et al., Cell Rep. 9 (2014): 1781-1797 [0951] Xu, J. et al., Breast Cancer Res Treat. 134 (2012): 531-541 [0952] Xu, X. et al., Tumour. Biol (2016b) [0953] Yafune, A. et al., Toxicol. Lett. 222 (2013): 295-302 [0954] Yang, B. et al., Tumour. Biol 36 (2015): 2111-2119 [0955] Yang, F. et al., Breast Cancer Res Treat. 145 (2014): 23-32 [0956] Yao, J. et al., Hepatology 51 (2010): 846-856 [0957] Yao, R. et al., Anticancer Res 27 (2007): 3051-3058 [0958] Yasui, W. et al., Gastric. Cancer 8 (2005): 86-94 [0959] Ye, B. G. et al., Oncotarget. (2016) [0960] Yencilek, F. et al., Anticancer Res 36 (2016): 707-711 [0961] Yi, J. M. et al., Clin Cancer Res. (2013) [0962] Yokota, T. et al., Acta Neuropathol. 111 (2006): 29-38 [0963] Yong, Z. W. et al., Sci. Rep. 4 (2014): 6073 [0964] You, J. et al., Hum. Pathol. 46 (2015): 1068-1077 [0965] Yu, J. et al., Oncogene 32 (2013): 307-317 [0966] Yue, C. et al., Int. J Cancer 136 (2015): 117-126 [0967] Zaremba, S. et al., Cancer Res. 57 (1997): 4570-4577 [0968] Zhang, F. et al., J Proteomics. 102 (2014a): 125-136 [0969] Zhang, J. F. et al., Zhongguo Shi Yan. Xue. Ye. Xue. Za Zhi. 22 (2014b): 909-913 [0970] Zhang, J. M. et al., Biochem. Biophys. Res Commun. 459 (2015): 252-258 [0971] Zhang, M. et al., Gynecol. Oncol 141 (2016a): 57-64 [0972] Zhang, N. et al., Oncotarget. (2016b) [0973] Zhang, W. et al., Cell Res 24 (2014c): 331-343 [0974] Zhang, X. et al., Med Oncol 30 (2013): 454 [0975] Zhao, J. et al., Int. J Clin Exp. Pathol. 8 (2015a): 10784-10791 [0976] Zhao, Y. F. et al., Biochem. Biophys. Res Commun. 456 (2015b): 232-237 [0977] Zhao, Z. et al., Breast Cancer Res 16 (2014): 408 [0978] Zheng, Y. et al., Clin Cancer Res 19 (2013): 6484-6494 [0979] Zhou, J. et al., Carcinogenesis 36 (2015): 441-451 [0980] Zhou, Q. et al., Onco. Targets. Ther. 9 (2016): 2749-2757 [0981] Zhu, M. et al., Nucleic Acids Res 42 (2014a): 13074-13081 [0982] Zhu, Z. et al., PLoS. One. 9 (2014b): e96576 [0983] Zong, G. et al., Dig. Dis. Sci. 61 (2016): 2303-2314 [0984] Zufferey, R. et al., J Virol. 73 (1999): 2886-2892