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

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cause of its ability to induce both anti-MUC-1 antibodies and CTL responses (reviewed in [309, 310]). However, soluble MUC-1 and -2 have been shown to be immunosuppressive tumor antigens. Accordingly, high serum levels of MUC-1 correlate with poor survival and enhanced metastatic disease for adenocarcinoma (breast, ovarian, pancreatic and colorectal) following active specific immunotherapy [311, 312]. Therefore, the release of MUC antigens from the surface of tumor cells might promote tumorigenesis and subvert the host immune system by two mechanisms: (1) release of MUC-1 by tumor cells would inhibit the effectiveness of the host anti-MUCspecific CTL response due to the down-regulation of specific tumor antigen expression and (2) release of tumor-associated MUC-1 molecules might have direct immunosuppressive effects on the host immune system. Mucins have been shown to inhibit T cell proliferation which can be reversed by IL-2 [313], suppress IL-2 [314] and IFN-g production by CD4 + T cells [314], and negatively regulate T cell activation at the resting stage [315]. Similarly, the soluble forms of annexin II and carcinoembryonic antigen (CEA), additional tumor-shed antigens, appear to function as immunosuppressive factors. Annexin is a membrane-associated glycoprotein expressed by normal and tumor cells [316, 317]. Annexin II expression has been correlated with higher grade tumors [318, 319] and poor prognosis in cancer patients [320]. In its soluble form, annexin II inhibits T cell proliferation [321], and suppresses IgG and IgM secretion from mononuclear cells [322]. CEA is another example of a ªtumor antigenº currently being evaluated for use in anticancer immunotherapeutic strategies. CEA is frequently present on colorectal tumors and circulating CEA levels correlate with poor survival rates [323]. The shedding of CEA from the surface of tumor cells has been proposed to serve as an immunosuppressive factor for LAK cytotoxic activity [324], as well as NK and Th1 cells [325]. Thus, multiple shed tumor-associated antigens may function as immunosuppressive agents. 7.7 Conclusion 7.7 Conclusion Unfortunately, the struggle between the host and the tumor often results in defeat for the host. Tumors escape the host's innate and acquired antitumor immune response through multiple and complex mechanisms. In many cases, tumors release factors including cytokines, lipids, polyamines and/or tumor-related antigens that suppress the host immune response, and at the same time stimulate tumor growth and survival. Much is known regarding how single tumor-derived suppressive factors impair various immune cell subtypes. However, the reported immunosuppressive effects of numerous factors are often inconsistent. These inconsistencies suggest that the effects of immunosuppressive factors on the host antitumor immune response depend on many factors, including the tumor type, tumor location, cytokine milieu, timing of the appearance of the suppressive factor, as well as the origin and state of activation of the specific immune cells. In addition, we do not understand how multiple tumor-derived immunosuppressive factors interact with immune cells to subvert the host immune system in vivo. Furthermore, it is unlikely that we have identi- 135
136 7 Immunosuppresive Factors in Cancer fied all of the tumor-derived immunosuppressive factors. Thus, more extensive studies are required to improve our understanding of how tumors suppress the host immune response. This information will be invaluable for the future development of improved therapeutics designed to block tumor-associated host immunosuppression in cancer patients and to improve host antitumor immunity using conventional cancer treatments and novel immunotherapeutic approaches. References 1 Assoian, R. K., C. A. Frolik, A. B. Roberts, D. M. Miller and M. B. Sporn. 1984. Transforming growth factor-b controls receptor levels for epidermal growth factor in NRK fibroblasts. Cell 36:35. 2 Roberts, A. B., M. A. Anzano, L. C. Lamb, J. M. Smith and M. B. Sporn. 1984. Antagonistic actions of retinoic acid and dexamethasone on anchorageindependent growth and epidermal growth factor binding of normal rat kidney cells. Cancer Res. 44: 1635. 3 Flanders, K. C. and A. B. Roberts. 2000. TGF-b. In: M. Feldmann, S. Durum, N. Nicola, J. Vilchek and T. Hiran (eds), Cytokine Reference. Academic Press, New York, p. 719. 4 Massague, J. 2000. How cells read TGF-b signals. Nat. Rev. Mol. Cell Biol 1: 169. 5 Fox, F. E., H. C. Ford, R. Douglas, S. Cherian and P. C. Nowell. 1993. Evidence that TGF-b can inhibit human T-lymphocyte proliferation through paracrine and autocrine mechanisms. Cell. Immunol. 150: 45. 6 Kehrl, J. H., A. B. Roberts, L. M. Wakefield, S. Jakowlew, M. B. Sporn and A. S. Fauci. 1986. Transforming growth factor b is an important immunomodulatory protein for human B lymphocytes. J. Immunol. 137: 3855. 7 Bellone, G., M. Aste-Amezaga, G. Trinchieri and U. Rodeck. 1995. Regulation of NK cell functions by TGF-b1. J. Immunol. 155: 1066. 8 von Bernstorff,W., M. Voss, S. Freichel, A. Schmid, I. Vogel, C. Johnk, D. Henne-Bruns, B. Kremer and H. Kalthoff. 2001. Systemic and local immunosuppression in pancreatic cancer patients. Clin. Cancer Res. 7: 925s. 9 Stravodimos, K., C. Constantinides, T. Manousakas, C. Pavlaki, D. Pantazopoulos, A. Giannopoulos and C. Dimopoulos. 2000. Immunohistochemical expression of transforming growth factor b1 and nm-23 H1 antioncogene in prostate cancer: divergent correlation with clinicopathological parameters. Anticancer Res. 20: 3823. 10 Cardillo, M. R., E. Petrangeli, L. Perracchio, L. Salvatori, L. Ravenna and F. Di Silverio. 2000. Transforming growth factor-b expression in prostate neoplasia. Anal. Quant. Cytol. Histol. 22:1. 11 Kang,Y., M. A. Prentice, J. M. Mariano, S. Davarya, R. I. Linnoila, T. W. Moody, L. M. Wakefield and S. B. Jakowlew. 2000. Transforming growth factor-b1 and its receptors in human lung cancer and mouse lung carcinogenesis. Exp. Lung Res. 26: 685. 12 Bellone, G., A. Carbone, D. Tibaudi, F. Mauri, I. Ferrero, C. Smirne, F. Suman, C. Rivetti, G. Migliaretti, M. Camandona, G. Palestro, G. Emanuelli and U. Rodeck. 2001. Differential expression of transforming growth factors-b1, -b2 and -b3 in human colon carcinoma. Eur. J. Cancer 37: 224. 13 Moretti, S., C. Pinzi, A. Spallanzani, E. Berti, A. Chiarugi, S. Mazzoli, M. Fabiani, C. Vallecchi and M. Herlyn. 1999. Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. Int. J. Cancer 84: 160. 14 Koli, K. M. and C. L. Arteaga. 1996. Complex role of tumor cell transforming growth factor (TGF)-bs on breast carcinoma progression. J. Mammary Gland. Biol. Neoplasia 1: 373.
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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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188 9 Dendritic Cells and Cancer: P
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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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