Abstract
Although antigen loss variants, major histocompatibility (MHC) class I down-regulation, or the expression of inhibitory molecules may explain the failure of immunosurveillance against some tumors, this seems not to apply for many other solid peripheral or lymphohematopoietic tumors. Why then is immunosurveillance so ineffective and can it be improved? This review focuses on one important aspect of tumor immunity, namely the relevance of antigen dose and localization. Immune responses in vivo are induced in organized lymphoid tissues, i.e., in lymph nodes and spleen. The antigen dose that reaches secondary lymphoid organs over time is a crucial parameter that drives antiviral and antitumoral immune responses. Tumors use various strategies to prevent efficient presentation of their antigens in lymphoid organs. A major obstacle to the induction of an endogenous tumor-specific cytotoxic T lymphocyte (CTL) response is the inefficient presentation of tumor antigen on MHC class I molecules of professional antigen-presenting cells. Peripheral solid tumors that develop outside lymphoid organs are, therefore, often ignored by the immune system. In other situations, tumors — especially of lymphohematopoietic origin — may tolerize specific CTLs. Understanding tumor immunosurveillance is key to the design of efficient antitumor vaccines. Attempts to improve immunity to tumors include vaccination strategies to (a) provide the tumor antigen to secondary lymphoid organs using recombinant viruses or dendritic cells as carriers, (b) express costimulatory signals on tumor cells, or (c) improve the efficiency of cross-priming.
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References
Bachmann MF, Zinkernagel RM . Neutralizing anti-viral B cell responses Annu Rev Immunol 1997 15: 235–270
Fenner F, McAuslan BR, Mims CA, Sambrook J, White DO . The Biology of Animal Viruses London: Academic Press 1974
Baumgarth N, Herman OC, Jager GC, Brown LE, Herzenberg LA, Chen J . B-1 and B-2 cell–derived immunoglobulin M antibodies are nonredundant components of the protective response to influenza virus infection J Exp Med 2000 192: 271–280
Zinkernagel RM, Bachmann MF, Kündig TM, Oehen S, Pircher H, Hengartner H . On immunological memory Annu Rev Immunol 1996 14: 333–367
Boon T, Coulie PG, Van DE . Tumor antigens recognized by T cells Immunol Today 1997 18: 267–268
Old LJ . Tumor immunology: the first century Curr Opin Immunol 1992 4: 603–607
Burnet FM . Cancer: a biological approach Br Med J 1957 1: 779–786
Burnet FM . Immunological aspects of malignant disease Lancet 1967 1: 1171–1174
Pardoll D . T cells and tumours Nature 2001 411: 1010–1012
Smyth MJ, Godfrey DI, Trapani JA . A fresh look at tumor immunosurveillance and immunotherapy Nat Immunol 2001 2: 293–299
Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA . Fas ligand–induced apoptosis as a mechanism of immune privilege Science 1995 270: 1189–1192
Garrido F, Ruiz-Cabello F, Cabrera T et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours Immunol Today 1997 18: 89–95
Chen JJ, Sun Y, Nabel GJ . Regulation of the proinflammatory effects of Fas ligand (CD95L) Science 1998 282: 1714–1717
Benitez R, Godelaine D, Lopez-Nevot MA et al. Mutations of the beta2-microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptides Tissue Antigens 1998 52: 520–529
Johnson A, France J, Sy MS, Harding CV . Down-regulation of the transporter for antigen presentation, proteasome subunits and MHC class I in tumor cell lines Cancer Res 1998 58: 3660–3667
Rosenberg SA, Spiess P, Lafreniere R . A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes Science 1986 233: 1318–1321
Whiteside TL . Tumor-infiltrating lymphocytes in human solid tumors Immunol Ser 1994 61: 137–148
Hiesse C, Rieu P, Kriaa F et al. Malignancy after renal transplantation: analysis of incidence and risk factors in 1700 patients followed during a 25-year period Transplant Proc 1997 29: 831–833
Newstead CG . Assessment of risk of cancer after renal transplantation Lancet 1998 351: 610–611
Kelly DM, Emre S, Guy SR, Miller CM, Schwartz ME, Sheiner PA . Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors Cancer 1998 83: 1237–1243
Stutman O . Immunodepression and malignancy Adv Cancer Res 1975 22: 261–422
Shankaran V, Ikeda H, Bruce AT et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity Nature 2001 410: 1107–1111
van den Broek MF, Kägi D, Ossendorp F et al. Decreased tumor surveillance in perforin-deficient mice J Exp Med 1996 184: 1781–1790
Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA . Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma J Exp Med 2000 192: 755–760
Houghton AN, Scheinberg DA . Monoclonal antibody therapies — a “constant” threat to cancer Nat Med 2000 6: 373–374
Carter P . Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer 2001 1: 118–129
Clynes R, Takechi Y, Moroi Y, Houghton A, Ravetch JV . Fc receptors are required in passive and active immunity to melanoma Proc Natl Acad Sci USA 1998 95: 652–656
Clynes RA, Towers TL, Presta LG, Ravetch JV . Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets Nat Med 2000 6: 443–446
Sampson JH, Crotty LE, Lee S et al. Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors Proc Natl Acad Sci USA 2000 97: 7503–7508
Idusogie EE, Presta LG, Gazzano-Santoro H et al. Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc J Immunol 2000 164: 4178–4184
Regnault A, Lankar D, Lacabanne V et al. Fcgamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I–restricted antigen presentation after immune complex internalization J Exp Med 1999 189: 371–380
Machy P, Serre K, Leserman L . Class I–restricted presentation of exogenous antigen acquired by Fcgamma receptor-mediated endocytosis is regulated in dendritic cells Eur J Immunol 2000 30: 848–857
Dhodapkar KM, Krasovsky J, Williamson B, Dhodapkar MV . Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells J Exp Med 2002 195: 125–133
Dyall R, Vasovic LV, Clynes RA, Nikolic-Zugic J . Cellular requirements for the monoclonal antibody-mediated eradication of an established solid tumor Eur J Immunol 1999 29: 30–37
Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T . B cells inhibit induction of T cell–dependent tumor immunity Nat Med 1998 4: 627–630
Ford WL . Lymphocyte migration and immune responses Prog Allergy 1975 19: 1–59
Mackay CR . T cell memory: the connection between function, phenotype and migration pathways Immunol Today 1991 12: 189–192
Zinkernagel RM, Ehl S, Aichele P, Oehen S, Kündig TM, Hengartner H . Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity Immunol Rev 1997 156: 199–209
Goodnow CC . Chance encounters and organized rendezvous Immunol Rev 1997 156: 5–10
Kündig TM, Bachmann MF, DiPaolo C et al. Fibroblasts as efficient antigen-presenting cells in lymphoid organs Science 1995 268: 1343–1347
Karrer U, Althage A, Odermatt B et al. On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11−/−) mutant mice J Exp Med 1997 185: 2157–2170
Ochsenbein AF, Sierro S, Odermatt B et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction Nature 2001 411: 1058–1064
Zinkernagel RM, Hengartner H . Regulation of the immune response by antigen Science 2001 293: 251–253
Ohashi PS, Oehen S, Buerki K et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice Cell 1991 65: 305–317
Chen L . Immunological ignorance of silent antigens as an explanation of tumor evasion Immunol Today 1998 19: 27–30
Frazer IH . Cell-mediated immunity to papilloma viruses Papillomavirus Rep 1992 3: 53–58
Frey JR, Wenk P . Experimental studies on the pathogenesis of contact eczema in the guinea-pig Int Arch Allergy 1957 11: 81–100
Lafferty KJ, Woolnough J . The origin and mechanism of allograft rejection Immunol Rev 1997 35: 231–262
Oldstone MB, Nerenberg M, Southern P, Price J, Lewicki H . Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response Cell 1991 65: 319–331
Ludewig B, Odermatt B, Landmann S, Hengartner H, Zinkernagel RM . Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue J Exp Med 1998 188: 1493–1501
Miyawaki S, Nakamura Y, Suzuka H et al. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice Eur J Immunol 1994 24: 429–434
Lakkis FG, Arakelov A, Konieczny BT, Inoue Y . Immunologic “ignorance” of vascularized organ transplants in the absence of secondary lymphoid tissue Nat Med 2000 6: 686–688
Ochsenbein AF, Klenerman P, Karrer U et al. Immune surveillance against a peripheral solid tumor fails because of immunological ignorance Proc Natl Acad Sci USA 1999 96: 2233–2238
DeVita VT, Hellmann S, Rosenberg SA . In: DeVita VT, Hellmann S, Rosenberg SA, eds Cancer, Principles and Practice of Oncology Philadelphia, USA: Lippincott Raven 1998 Vol. 5:
Webb S, Morris C, Sprent J . Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity Cell 1990 63: 1249–1256
Moskophidis D, Lechner F, Pircher H, Zinkernagel RM . Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells Nature 1993 362: 758–761
Staveley-O'Carrol K, Sotomayor E, Montgomery J et al. Induction of antigen-specific T cell anergy: an early event in the course of tumor progression Proc Natl Acad Sci USA 1998 95: 1178–1183
Bretscher P, Cohn M . A theory of self-nonself discrimination Science 1970 169: 1042–1049
Lafferty KJ, Cunningham AJ . A new analysis of allogeneic interactions Aust J Exp Biol Med Sci 1975 53: 27–42
Schwartz RH . A cell culture model for T lymphocyte clonal anergy Science 1990 248: 1349–1356
Chen L, Ashe S, Brady WA et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4 Cell 1992 71: 1093–1102
Townsend SE, Allison JP . Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells Science 1993 259: 368–370
Matzinger P . Tolerance, danger, and the extended family Annu Rev Immunol 1994 12: 991–1045
Chambers CA, Allison JP . Co-stimulation in T cell responses Curr Opin Immunol 1997 9: 396–404
Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G . Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T–T help via APC activation J Exp Med 1996 184: 747–752
Diehl L, Den BA, Schoenberger SP et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy Nat Med 1999 5: 774–779
Hintzen RQ, de JR, Lens SM, van LR . CD27: marker and mediator of T-cell activation? Immunol Today 1994 15: 307–311
Watts TH, DeBenedette MA . T cell co-stimulatory molecules other than CD28 Curr Opin Immunol 1999 11: 286–293
Smith KA . Interleukin 2 Annu Rev Immunol 1984 2: 319–333
Shimizu Y, van SG, Horgan KJ, Shaw S . Roles of adhesion molecules in T-cell recognition: fundamental similarities between four integrins on resting human T cells (LFA-1, VLA-4, VLA-5, VLA-6) in expression, binding, and costimulation Immunol Rev 1990 114: 109–143
Liebowitz DN, Lee KP, June CH . Costimulatory approaches to adoptive immunotherapy Curr Opin Oncol 1998 10: 533–541
Hellstrom KE, Hellstrom I, Chen L . Can co-stimulated tumor immunity be therapeutically efficacious? Immunol Rev 1995 145: 123–145
Melero I, Shuford WW, Newby SA et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors Nat Med 1997 3: 682–685
Shahinian A, Pfeffer K, Lee KP et al. Differential T cell costimulatory requirements in CD28-deficient mice Science 1993 261: 609–612
Yang G, Mizuno MT, Hellstrom KE, Chen L . B7-negative versus B7-positive P815 tumor. Differential requirements for priming of an antitumor immune response in lymph nodes J Immunol 1997 158: 851–858
Ramarathinam L, Castle M, Wu Y, Liu Y . T cell costimulation by B7/BB1 induces CD8 T cell–dependent tumor rejection: an important role of B7/BB1 in the induction, recruitment, and effector function of antitumor T cells J Exp Med 1994 179: 1205–1214
Maric M, Zheng P, Sarma S, Guo Y, Liu Y . Maturation of cytotoxic T lymphocytes against a B7-transfected nonmetastatic tumor: a critical role for costimulation by B7 on both tumor and host antigen-presenting cells Cancer Res 1998 58: 3376–3384
Chang TT, Jabs C, Sobel RA, Kuchroo VK, Sharpe AH . Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phase of experimental autoimmune encephalomyelitis J Exp Med 1999 190: 733–740
Harlan DM, Hengartner H, Huang ML et al. Mice expressing both B7-1 and viral glycoprotein on pancreatic beta cells along with glycoprotein-specific transgenic T cells develop diabetes due to a breakdown of T-lymphocyte unresponsiveness Proc Natl Acad Sci USA 1994 91: 3137–3141
Bevan MJ . Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay J Exp Med 1976 143: 1283–1288
Carbone FR, Kurts C, Bennet SRM, Miller JFAP, Heath WR . Cross-presentation: a general mechanism for CTL immunity and tolerance Immunol Today 1998 19: 368–373
Albert ML, Sauter B, Bhardwaj N . Dendritic cells acquire antigen from apoptotic cells and induce class I–restricted CTLs Nature 1998 392: 86–89
Sigal LJ, Crotty S, Andino R, Rock KL . Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen Nature 1999 398: 77–80
Heath WR, Carbone FR . Cross-presentation in viral immunity and self-tolerance Nat Rev Immunol 2001 1: 126–134
Steinman RM, Turley S, Mellman I, Inaba K . The induction of tolerance by dendritic cells that have captured apoptotic cells J Exp Med 2000 191: 411–416
Heath WR, Carbone FR . Cross-presentation, dendritic cells, tolerance and immunity Annu Rev Immunol 2001 19: 47–64
Berard F, Blanco P, Davoust J et al. Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells J Exp Med 2000 192: 1535–1544
Shen Z, Reznikoff G, Dranoff G, Rock KL . Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules J Immunol 1997 158: 2723–2730
Kurts C, Miller JF, Subramaniam RM, Carbone FR, Heath WR . Major histocompatibility complex class I–restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction J Exp Med 1998 188: 409–414
Gordon RD, Mathieson BJ, Samelson LE, Boyse EA, Simpson E . The effect of allogeneic presensitization on H-Y graft survival and in vitro cell-mediated responses to H-Y antigen J Exp Med 1976 144: 810–820
Matzinger P, Bevan MJ . Induction of H-2–restricted cytotoxic T cells: in vivo induction has the appearance of being unrestricted Cell Immunol 1977 33: 92–100
Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H . Role of bone marrow–derived cells in presenting MHC class I–restricted tumor antigens Science 1994 264: 961–965
Toes RE, Ossendorp F, Offringa R, Melief CJ . CD4 T cells and their role in antitumor immune responses J Exp Med 1999 189: 753–756
Kurts C, Heath WR, Carbone FR, Allison J, Miller JFAP, Kosaka H . Constitutive class I–restricted exogenous presentation of self antigens in vivo J Exp Med 1996 184: 923–930
Shlomchik WD, Couzens MS, Tang CB et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells Science 1999 285: 412–415
Pardoll DM . Spinning molecular immunology into successful immunotherapy Nat Rev Immunol 2002 2: 227–238
Smyth MJ, Godfrey DI, Trapani JA . A fresh look at tumor immunosurveillance and immunotherapy Nat Immunol 2001 2: 293–299
Riddell SR, Greenberg PD . Principles for adoptive T cell therapy of human viral diseases Annu Rev Immunol 1995 13: 545–586
Nestle FO, Banchereau J, Hart D . Dendritic cells: on the move from bench to bedside Nat Med 2001 7: 761–764
Jager E, Gnjatic S, Nagata Y et al. Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers Proc Natl Acad Sci 2000 97: 12198–12203
Parmiani G, Castelli C, Dalerba P et al. Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? J Natl Cancer Inst 2002 94: 805–818
Coulie PG, Karanikas V, Colau D et al. A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3 Proc Natl Acad Sci USA 2001 98: 10290–10295
Reyes-Sandoval A, Ertl HC . DNA vaccines Curr Mol Med 2001 1: 217–243
Maloy KJ, Erdmann I, Basch V et al. Intralymphatic immunization enhances DNA vaccination Proc Natl Acad Sci USA 2001 98: 3299–3303
Marchand M, van BN, Weynants P et al. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1 Int J Cancer 1999 80: 219–230
Ramshaw IA, Ramsay AJ . The prime–boost strategy: exciting prospects for improved vaccination Immunol Today 2000 21: 163–165
Ludewig B, Ochsenbein AF, Odermatt B, Paulin D, Hengartner H, Zinkernagel RM . Immunotherapies with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease J Exp Med 2000 191: 795–804
Speiser DE, Miranda R, Zakarian A et al. Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: implications for immunotherapy J Exp Med 1997 186: 645–653
Kim JJ, Bagarazzi ML, Trivedi N et al. Engineering of in vivo immune responses to DNA immunization via codelivery of costimulatory molecule genes Nat Biotechnol 1997 15: 641–646
Weinberg AD, Rivera MM, Prell R et al. Engagement of the OX-40 receptor in vivo enhances antitumor immunity J Immunol 2000 164: 2160–2169
Bansal-Pakala P, Jember AG, Croft M . Signaling through OX40 (CD134) breaks peripheral T-cell tolerance Nat Med 2001 7: 907–912
Chen W, Carbone FR, McCluskey J . Electroporation and commercial liposomes efficiently deliver soluble protein into the MHC class I presentation pathway. Priming in vitro and in vivo for class I–restricted recognition of soluble antigen J Immunol Methods 1993 160: 49–57
Nakanishi T, Hayashi A, Kunisawa J et al. Fusogenic liposomes efficiently deliver exogenous antigen through the cytoplasm into the MHC class I processing pathway Eur J Immunol 2000 30: 1740–1747
Mandal M, Lee KD . Listeriolysin O-liposome–mediated cytosolic delivery of macromolecule antigen in vivo: enhancement of antigen-specific cytotoxic T lymphocyte frequency, activity, and tumor protection Biochim Biophys Acta 2002 1563: 7–17
Binder RJ, Han DK, Srivastava PK . CD91: a receptor for heat shock protein gp96 Nat Immunol 2000 1: 151–155
Schild H, Arnold-Schild D, Lammert E, Rammensee HG . Stress proteins and immunity mediated by cytotoxic T lymphocytes Curr Opin Immunol 1999 11: 109–113
Jeannin P, Renno T, Goetsch L et al. OmpA targets dendritic cells, induces their maturation and delivers antigen into the MHC class I presentation pathway Nat Immunol 2000 1: 502–509
Carroll MW, Overwijk WW, Chamberlain RS, Rosenberg SA, Moss B, Restifo NP . Highly attenuated modified vaccinia virus Ankara (MVA) as an effective recombinant vector: a murine tumor model Vaccine 1997 15: 387–394
Elzey BD, Siemens DR, Ratliff TL, Lubaroff DM . Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors Int J Cancer 2001 94: 842–849
Velders MP, McElhiney S, Cassetti MC et al. Eradication of established tumors by vaccination with Venezuelan equine encephalitis virus replicon particles delivering human papillomavirus 16 E7 RNA Cancer Res 2001 61: 7861–7867
Ada G . Vaccines and vaccination N Engl J Med 2001 345: 1042–1053
Irvine KR, Chamberlain RS, Shulman EP, Surman DR, Rosenberg SA, Restifo NP . Enhancing efficacy of recombinant anticancer vaccines with prime/boost regimens that use two different vectors J Natl Cancer Inst 1997 89: 1595–1601
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I thank Rolf Zinkernagel and William Ho for critically reading the manuscript. A F O was supported by the Swiss National Science Foundation (Grant 1078).
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Ochsenbein, A. Principles of tumor immunosurveillance and implications for immunotherapy. Cancer Gene Ther 9, 1043–1055 (2002). https://doi.org/10.1038/sj.cgt.7700540
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