Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

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eacted against 10 tumor-specific antigens, in association with eight different HLA molecules. They also revealed the existence of many unknown epitopes derived from 12 different melanoma associated antigens. In conclusion, these studies attest to the selective accumulation of tumor antigen-specific CD8 + T cells at the tumor site. The dynamics of their interactions with tumor cells and the tumor stroma remain to be studied in detail. 4.5 CD4 T Cells in Tumor Immunity 4.5 CD4 T Cells in Tumor Immunity Despite the central role that CD8 + T cell responses have in tumor immunity, there is growing evidence supporting an important role for CD4 + T cells. Murine studies have clearly shown that CD4 + T cells mediate antitumor activity through various mechanisms. First, through the induction phase of antigen-specific CD8 + T cells and of B cells. They also exert direct and indirect effects on tumor cells, even in those that are deficient in MHC class II expression [73]. Initial evidence of CD4 + T cell involvement in antitumor immunity in humans came from studies at the tumor site [74, 75]. An indirect indication of the involvement of CD4 + T cells in immunity against tumor is the detection of tumor-specific IgGs antibodies in cancer patients [28]. As with CD8 + Tcells, direct proof of the existence of tumor antigen-specific CD4 + T cell immunity came finally with the identification of several targets of these cells in human tumors. The first epitope identified corresponded to non-mutated peptide of the tyrosinase protein and presented by HLA-DR [76, 77]. Since then the list of MHC class II-restricted T cell epitopes has been growing steadily. In particular, CD4 + T cells recognizing tumor epitopes derived from tyrosinase [77], gp100 [78, 79], triosephosphate isomerase, CDC27, LDLR-FUT [80], MAGE-A3 [81±83], NY-ESO-1 [84±86] and Melan-A/MART-1[87] gene products have been identified (Tab. 4.2). There are several interesting aspects in the knowledge accumulated so far on the CD4 T cell responses to tumor-associated antigens. For instance, tumors need not express MHC class II molecules on their surface. Thus, the priming of the response is likely to have taken place via cross-presentation involving endogenous antigen-presenting cells. The second observation is that several of the CD4 T cell clones or lines have the ability to recognize directly the tumor cells that do express the MHC class II molecule presenting the antigenic peptide. Such is the case for MAGE-3-specific T cells directed against a peptide presented in association with HLA-DP4. Interestingly, however, another peptide derived from the same protein and presented by HLA-DR molecules does not appear to be presented at the surface of tumor cells as the corresponding specific CD4 T cells fail to recognize the tumor. The third point that deserves consideration is the evidence that DP molecules are functional in antigen presentation, an issue that was controversial until recently. This unexpected outcome may have important practical implications for immunotherapy. Indeed, while most of the HLA-DRB alleles occur at low frequency in the population, the HLA- DPB genes have limited polymorphism and the two major alleles, HLA-DPB1*0401 and *0402, are expressed in about 60±70% of the Caucasian population as well as in 49
50 4 T Cells In Tumor Immunity Tab. 4.2 MHC class II-restricted T cell epitopes expressed by human tumors Gene HLA allele Antigenic peptide sequence Category Reference MAGE-A3 DRB1*1101 TSYVKVLHHMVKISG shared tumor 82 specific MAGE-A1, DRB1*1301, *1302 LLKYRAREPVTKAE 99 -A2, -A3, -A6 MAGE-A3 DRB1*1301, *1302 AELVHFLLLKYRAR 81 MAGE-A3 DPB1*0401, *0402 TQHFVQENYLEY 83 NY-ESO-1DRB4*0101 VLLKEFTVSG 84 NY-ESO-1 DRB4*0101±0103 PLPVPGVLLKEFTVSGNI 85 VLLKEFTVSGNILTIRLT AADHRQLQLSISSCLQQL NY-ESO-1DPB1*0401 SLLMWITQCFLPVF 86 Tyrosinase DRB1*0401 QNILLSNAPLGPQFP differentiation 76 Tyrosinase DRB1*0401 SYLQDSDPDSFQD 77 Tyrosinase DRB1*1501 RHRPLQEVYPEANAPIGHNRE 100 Melan-A/ DRB1*0401 RNGYRALMDKSLHVGTQCALTRR 87 MART-1 Gp100 DRB1*0401 WNRQLYPEWTEAQRLD 78, 79 PSA DR4 ILLGRMSLFMPEDTG 101 SLFHPEDTGQVFQ QVFQVSHSFPHPLYD NDLMLLRLSEPAELT KKLQCVQLHVISM GVLQGITSMGSEPCA CDC27 DRB1*0401 FSWAMDLDPKGA mutated/unique 80 TPI DRB1*0101 GELIGILNAAKVPAD 102 HPV59-E7 DRB1*0401 LFMDTLSFVCPLC viral 103 HPV68-E7 DRB1*0407 LFMDSLNFVCPWC MUC-1DR3 PGSTAPPAHGVT over-expressed 104 other ethnic groups. Thus, the MAGE-A3 and NY-ESO-1HLA-DP4-restricted T cell epitopes constitute attractive targets for vaccination. It is going to be interesting in the future to identify additional DP4-restricted epitopes from tumor-associated proteins that have a wide expression in many tumor types. Such targets would indeed cover large segments of the population and help reduce the highly individualized nature of many tumor antigen-based vaccines. Finally, direct monitoring of tumor antigen-specific CD4 + T cell responses is its infancy. There are no MHC class II tetramers with tumor antigenic peptides reported yet. Efforts in several laboratories in this direction are underway. Tetramers with a few class II molecules have been successfully generated. For instance, mouse I-A d [88], I-E k [89], human HLA-DR1[90], HLA-DR4 [91, 92] and HLA-DQ [93]. Future analyses of the natural or induced class II-restricted antitumor immune responses should greatly benefit from the ability to use fluorescent class II MHC/peptide tetramers.
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Cancer Immune Therapie: Current and
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Editors: Dr. Gernot Stuhler Univers
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VI Preface Recent years have seen a
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VIII Contents 2.5.3 Antigens Encode
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X Contents 6.4.2 Natural Killer (NK
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XII Contents 9.6 Loading DC with An
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XIV Contents 14.2.2.1 Cancer-specif
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List of Contributors Richard Bucala
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Color Plates Fig. 5.2 The MHC class
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Fig. 5.5 Different immune effector
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Fig. 5.17 Possible pathway for the
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Fig. 6.2 T lymphocytes in the tumor
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Index a acidic and basic fibroblast
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±, see also tumors cationic lipids
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e EBV see Epstein-Barr virus EDR se
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immature Mo-DCs 184 immune cells ±
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MHC class I antigen-processing mach
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Page 37 and 38: TICD see tumor-induced cell death T
Page 39 and 40: Part 1 Tumor Antigenicity Cancer Im
Page 41 and 42: 4 1 Search for Universal Tumor-Asso
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Page 67 and 68: 30 Cancer Immune Therapie: Current
Page 69 and 70: 32 3 Processing and Presentation of
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Page 79 and 80: 42 4 T Cells In Tumor Immunity cult
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Page 91 and 92: 54 4 T Cells In Tumor Immunity 53 T
Page 93 and 94: Part 2 Immune Evasion and Suppressi
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102 6 Immune Cells in the Tumor Mic
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Tab. 7.1 Effects of tumor-derived m
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122 7 Immunosuppresive Factors in C
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156 8 Interleukin-10 in Cancer Immu
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Part 3 Strategies for Cancer Immuno
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180 9 Dendritic Cells and Cancer: P
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204 Cancer Immune Therapie: Current
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206 10 The Immune System in Cancer:
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232 11 Hybrid Cell Vaccination for
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254 12 Principles and Strategies Em
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270 13 Applications of CpG Motifs f
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288 14 The T-Body Approach: Towards
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300 15 Bone Marrow Transplantation
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312 16 Immunocytokines: Versatile M
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348 17 Immunotoxins and Recombinant
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382 Glossary tion to the variable d
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384 Glossary suppressor gene produc
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386 Glossary press the proper recep
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388 Glossary gp96 See Chaperone. Gr
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390 Glossary cytes and addressing l
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392 Glossary T bodies are being tes
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