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

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10.6 Exploiting Weaknesses: Autoimmunity tiple sclerosis could be identified, perhaps it could be used in a modified form or context as an adjuvant for tumor vaccination (although clearly whatever the context, or form, of the agent is that promotes multiple sclerosis would have to be nullified). Many autoimmune diseases also proceed through a series of cycles of relapse and remission, perhaps stimulated by periodic trauma or episodes of inflammation. Might immunotherapies directed against predominantly self or near-self tumor antigens be most effective if given as repeated vaccinations to overcome the natural waning of T cell responses [37]? We should, therefore, be able to learn a great deal about how to induce tumor immunity by understanding how the immune system is duped during autoimmune disease initiation and progression. 217
218 10 The Immune System in Cancer: If It Isn't Broken, Can We Fix It? 10.7 Combining the Best of Both Worlds It is already clear from both in vitro and in vivo tumor model systems [31±35, 38, 39], as well as from clinical experience of autoimmune disease, that the immune system can be re-educated to recognize self/near-self antigens to the point of mounting clearative immune responses against them. In fact, a surprisingly wide variety of different approaches (Fig. 10.6) have proved effective in animal models of tumor rejection [4, 5, 12, 40±56]. The literature of tumor immunotherapy in (transplantable) rodent models (i.e. immunocompetent mice injected with tumor cells derived from syngeneic mice) is so full of different success stories that it would seem that curing cancer in mice is little more than a case of choose your gene and use it! Yet immunotherapy in human oncology remains only very much at the periphery of clinical utility [57]. This discrepancy highlights the deficiencies of the animal models of tumorigenesis that have been used in the past and, in reality, such systems may more faithfully represent models of parasitic infections than growth of human tumors. This is because many of the tumor cell lines used to establish tumors in animal models have been passaged for many years in tissue culture and may have lost many of the characteristics that define true tumors which develop over time in the presence of an intact host immune system [58]. Nonetheless, despite criticisms of the models used, it is now possible to rationalize the apparently highly diverse range of successful approaches into a few common principles. Most successful immunotherapies for cancer culminate in a common pathway that starts by tumor cell killing (Figs 10.5B and 10.6). Tumor cell killing can be achieved in many ways ± directly by cytotoxic gene expression or indirectly through activation of both specific (T cells) or non-specific [59] (natural killer, eosinophils, macrophages) immune mechanisms through expression of co-stimulatory molecules, adjuvants, cytokines, immunogens and so on (Figs 10.5B and 10.6). However, not all tumor cell death is equal [9, 37, 60±63]. In general, it is not only important to kill tumor cells, but to make sure that they `suffer' as they die, i. e. that they show biochemical markers of a `stressful death' [60]. This labels them as `pathologically abnormal' to the immune system (Fig. 10.4A) ± distinguishing them from cells that are undergoing `normal' cell death, such as occurs during development [9, 37, 64]. In particular, cells dying a stressful death express heat shock proteins [48, 60, 62, 65] and cause the unhindered [60, 66] release of intracellular molecules that are natural activators of DCs [61, 63, 67, 68] (Fig. 10.5B). By contrast, `normal` cell death is likely to lead both to induction of tolerance to cellular antigens at the level of DC function [6] and to the neat packaging and removal of all of these materials by phagocytes before they can signal immunological danger (see Appendix) [37, 60, 66, 69±71]. There is also a fine balance between the mechanisms of cell death and the levels of that death. Even if cells die a stress-free death by apoptosis, if the levels of apoptosis are too high for phagocytes to clear up the debris, autoimmune pathology results [72, 73]. It might be possible to exploit the reactions to this form of cell death for antitumor vaccination [74, 75]: if a good source of tumor antigen is available, then
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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
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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
Page 287 and 288: 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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