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

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these epitopes. However, any T cells which can bind an epitope through presentation by an activated APC will now recognize any cell that displays these epitopes on their surface class I molecules. This then illustrates the critical link between the uptake of antigen by APC in a fully co-stimulatory environment, and the subsequent effector phase of target cell recognition and killing by fully activated T cells. In the case of tumor antigens, therefore, the antigen displayed by the tumor cell in the context of MHC class I needs to be recognized by peripheral T cells bearing TCRs with the acuity to bind the epitopes derived from the mutated regions of these proteins, whilst distinguishing these from epitopes derived from wild-type versions of the proteins (Fig. 10.3). One type of tumor antigen that stands a high chance of doing this is one that contains novel epitopes created by fusion of self proteins, such as the Bcr±Abl junction fragment [5]. However, as we discussed above, many oncogenic mutations are very subtle (e.g. point mutations in oncoproteins such as Ras). There are likely to be only a few T cells with TCRs which have the fine structure to distinguish a self from a near-self epitope (Fig. 10.3B), unless the changes in the nearself epitope are very significant. Any such T cells would be critically valuable in clearing tumor cells, but not related, normal cells (Fig. 10.3C). In addition, a small number of peripheral T cells might retain the ability to recognize unaltered self epitopes, There are three reasons why this might occur: (1) a self antigen might resemble a foreign antigen ± a phenomenon known as molecular mimicry (see Appendix), (2) T cells carrying low-affinity TCR for an antigen might have been overlooked by the process of thymic deletion as described in Box 10.1 and Fig. 10.3 or (3) there might be a lack of central tolerance to the antigen because it is inaccessible to thymic APCs during the formation of the T cell repertoire [6]. Therefore, the T cell armory available for the war on cancer is probably populated by T cells carrying, at best, TCRs that can only weakly recognize subdominant epitopes (see Appendix) of self proteins and/or weakly immunogenic epitopes of TAAs derived from mutated self proteins (Fig. 10.3). The existence of such T cells is tolerated (Box 10.1) because even if they become inadvertently activated to recognize self antigens, that recognition might not lead to catastrophic autoimmune disease. An example of this is vitiligo, the skin depigmentation that occurs in some patients undergoing treatment with melanoma vaccines, when an effective immune response is generated not only against the melanoma cells, but also against melanocytes [7]. It is this army of ªsecond-rateº Tcells that we must collaborate with in devising antitumor immunization strategies (Fig. 10.3). The next question, then, is how we manipulate these intrinsically weak responses to make them resemble responses to truly foreign antigens. 10.5 Playing to Strengths 10.5 Playing to Strengths In the immune responses against pathogenic infection, the immune system is working against a set of clearly defined, outstandingly foreign antigens. These antigens are usually associated with overtly inflammatory, pathological situations ± such as 211
212 10 The Immune System in Cancer: If It Isn't Broken, Can We Fix It? Fig. 10.4 Lessons for tumor immunotherapy from normal immune function. (A) What the immune system does well. An invading pathogen activates non-specific immune effectors such as natural killer cells, macrophages and eosinophils. This releases cellular contents and foreign antigens into a highly immunostimulatory environment that recruits and activates APCs such as DCs. Uptake, processing and presentation of the tumor antigens in this environment occurs in the presence of full co-stimulation (adhesion molecules and those of the B7 family). This presentation activates a large pool of T cells with receptors (TCRs) that can recognize foreign epitopes from the pathogen's proteins. (B) What the immune system does poorly. In the case of tumor growth, there is normally no invading pathogen and little or no physiologically abnormal cell death. Any antigen that is released is either self or near-self. Therefore, even if these antigens are ingested by APCs they are presented in an immunosuppressive environment lacking co-stimulation. Very few T cells have TCRs that can recognize tumor-associated epitopes and any T cells bearing these TCRs are likely to be rendered anergic by presentation of the epitopes in the absence of full APC activation.
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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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±, onco- 209 ±, over-expressed ce
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TICD see tumor-induced cell death T
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Part 1 Tumor Antigenicity Cancer Im
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4 1 Search for Universal Tumor-Asso
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10 1 Search for Universal Tumor-Ass
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18 2 Serological Determinants On Tu
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30 Cancer Immune Therapie: Current
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32 3 Processing and Presentation of
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42 4 T Cells In Tumor Immunity cult
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44 4 T Cells In Tumor Immunity cell
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46 4 T Cells In Tumor Immunity to T
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48 4 T Cells In Tumor Immunity Alth
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50 4 T Cells In Tumor Immunity Tab.
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52 4 T Cells In Tumor Immunity rest
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54 4 T Cells In Tumor Immunity 53 T
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Part 2 Immune Evasion and Suppressi
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60 5 Major Histocompatibility Compl
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68 Tab. 5.1 HLA class I loss attrib
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96 6 Immune Cells in the Tumor Micr
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98 6 Immune Cells in the Tumor Micr
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100 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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Page 211 and 212: Part 3 Strategies for Cancer Immuno
Page 213 and 214: 180 9 Dendritic Cells and Cancer: P
Page 237 and 238: 204 Cancer Immune Therapie: Current
Page 239 and 240: 206 10 The Immune System in Cancer:
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Page 263 and 264: 230 Cancer Immune Therapie: Current
Page 265 and 266: 232 11 Hybrid Cell Vaccination for
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262 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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