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

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gp96 on tumor cells renders them regressive via a T lymphocyte-dependent mechanism. This work not only demonstrated that surface expression of gp96 has a profound influence on immunity, but also reinforced the notion that gp96 is an endogenous DC activator. Therefore, extracellular expression of HSPs might be an effective way to bridge innate and adaptive immunity for cancer immunotherapy. 12.3 Conclusion and Perspectives 12.3 Conclusion and Perspectives Although the immunological features of HSPs have been discovered in the context of defining tumor antigens, it is now clear that HSPs play far-reaching roles in the immune responses. The story of HSPs is somewhat analogous to that of MHC molecules. The MHC was discovered as a major transplant barrier, but its ªnaturalº role actually lies in antigen presentation. Different from HSPs, the function of MHC is almost exclusively immunological with a few exceptions [89, 90], which permits the creation of innovative animal models and sophisticated genetic studies. The study of HSPs so far still relies on biochemistry, i.e. purification of HSPs and testing the immunological properties of purified materials. This situation must change in order to address the fundamental roles of HSPs in the physiological context. There are still many unanswered questions. (1) What are the roles of HSPs in antigen presentation? It has been proposed that various HSPs constitute a relay line for peptide transfer from proteasome to MHC I molecules [91]. However, this point has not been firmly proven even though HSPs are peptide-binding proteins and there are generally no free-flowing peptides in the cells [54]. Inhibition of peptide binding of HSP70 by 15-deoxyspergualin inhibits antigen presentation to MHC class I [92], which is consistent with the roles of HSP70 in antigen presentation; however, the finding could also be explained by the roles of HSP70 in other cellular processes unrelated to peptide binding. The major obstacles are lack of systems where each member of the HSPs can be specifically manipulated and examined, and the fact that HSPs are essential for life. (2) Are HSPs involved in cross-presenting peptides to thymic T cells for positive or negative selection? This is a logical question since if HSPs are indeed involved in the priming of T cells, it should be expected that distal release of HSP±peptide complexes (as a result of cell death or active secretion) in the neonatal period might contribute to thymic T cell selection. This question has never been examined, perhaps due to lack of a good experimental model. (3) What are the contributions of HSPs to peripheral tolerance? The proponents for the roles of HSPs in priming adaptive immunity have not examined this issue in conditions where HSPs are released constantly, such as in patients with burns, trauma, peripheral vascular diseases and infections. Similarly, the roles of HSPs in immunopathology have not been carefully studied. 263
264 12 Principles and Strategies Employing Heat Shock Proteins for Immunotherapy of Cancers Despite all of these questions, the clinical development of HSPs in the treatment of malignancies is already in full swing. This effort must be encouraged in closely monitored settings since there are limited treatment modalities for most human cancers. However, one must be cautious that unless the roles and mechanisms of HSPs in immune response are well defined, it is certain that the clinical translations will face many uncertainties. References 1 F. M. Burnet, Prog Exp Tumor Res 1970; 13: 1±27. 2 H. Schreiber, in Fundamental Immunology, 4th edn (W. E. Paul, Ed.). Lippincott-Raven, Philadelphia, PA 1999: 1237±1270. 3 P. K. Srivastava, A. Menoret, S. Basu, R. J. Binder and K. L. McQuade, Immunity 1998; 8: 657±665. 4 S. Lindquist and E. A. Craig, Annu Rev Genet 1988; 22: 631±677. 5 M. E. Feder and G. E. Hofmann, Annu Rev Physiol 1999; 61: 243±282. 6 P. Csermely, T. Schnaider, C. Soti, Z. Prohaszka and G. Nardai, Pharmacol Ther 1998; 79: 129±168. 7 J. Frydman, Annu Rev Biochem 2001; 70: 603±647. 8 R. I. Morimoto, Genes Dev 1998; 12: 3788±3796. 9 Z. Li, Semin Immunol 1997; 9: 315±322. 10 C. Gaudin, F. Kremer, E. Angevin, V. Scott and F. Triebel, J Immunol 1999; 162: 1730±1738. 11 P. K. Srivastava and M. Heike, Semin Immunol 1991; 3: 57±64. 12 P. K. Srivastava and R. G. Maki, Curr Topics Microbiol Immunol 1991; 167: 109±123. 13 T. J. Nieland, M. C. Tan, M. Monnevan Muijen, F. Koning, A. M. Kruisbeek and G. M. van Bleek, Proc Natl Acad Sci USA 1996; 93: 6135±6139. 14 D. Arnold, S. Faath, H. Rammensee and H. Schild, J Exp Med 1995; 182: 885±889. 15 M. Breloer, T. Marti, B. Fleischer and A. von Bonin, Eur J Immunol 1998; 28: 1016±1021. 16 S. Nair, P. A. Wearsch, D. A. Mitchell, J. J. Wassenberg, E. Gilboa and C. V. Nicchitta, J Immunol 1999; 162: 6426±6423. 17 T. Ishii, H. Udono, T. Yamano, H. Ohta, A. Uenaka, T. Ono, A. Hizuta, N. Tanaka, P. K. Srivastava and E. Nakayama, J Immunol 1999; 162: 1303±1309. 18 S. D. Meng, T. Gao, G. F. Gao and P. Tien, Lancet 2001; 357: 528±529. 19 P. A. Wearsch, L. Voglino and C. V. Nicchitta, Biochemistry 1998; 37: 5709±5719. 20 S. Sastry and N. Linderoth, J Biol Chem 1999; 274: 12023±12035. 21 N. A. Linderoth, A. Popowicz and S. Sastry, J Biol Chem 2000; 275: 5472± 5477. 22 N. A. Linderoth, M. N. Simon, J. F. Hainfeld and S. Sastry, J Biol Chem 2001; 276: 11049±11054. 23 N. A. Linderoth, M. N. Simon, N. A. Rodionova, M. Cadene, W. R. Laws, B. T. Chait and S. Sastry, Biochemistry 2001; 40: 1483±1495. 24 G. C. Flynn, T. G. Chappell and J. E. Rothman, Science 1989; 245: 385± 390. 25 H. Udono and P. K. Srivastava, J Exp Med 1993; 178: 1391±1396. 26 C. Castelli, A. M. Ciupitu, F. Rini, L. Rivoltini, A. Mazzocchi, R. Kiessling and G. Parmiani, Cancer Res 2001; 61: 222±227. 27 X. Zhu, X. Zhao,W. F. Burkholder, A. Gragerov, C. M. Ogata, M. E. Gottesman and W. A. Hendrickson, Science 1996; 272: 1606±1614. 28 D. Arnold-Schild, D. Hanau, D. Spehner, C. Schmid, H. G. Rammensee, H. de la Salle and H. Schild, J Immunol 1999; 162: 3757±3760. 29 J. J. Wassenberg, C. Dezfulian and
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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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Part 3 Strategies for Cancer Immuno
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180 9 Dendritic Cells and Cancer: P
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206 10 The Immune System in Cancer:
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Page 245 and 246: 212 10 The Immune System in Cancer:
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Page 303 and 304: 270 13 Applications of CpG Motifs f
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314 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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