Abstract
Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, the immune surveillance against clinically manifest carcinomas and sarcomas seems relatively inefficient. Naïve cytotoxic T cells are activated exclusively in secondary lymphoid organs including the spleen and lymph nodes. Tumor antigen might be either cross-presented to naïve cytotoxic T cells by professional antigen-presenting cells (pAPC), or presented directly by tumor cells that migrated to secondary lymphoid organs. Direct priming is quite inefficient during early tumor development because metastasis to lymphoid organs is usually limited to advanced stage diseases. Similarly, the process of cross-priming by pAPC seems to depend on relatively large antigen amounts and on maturation stimuli for dendritic cells, and both requirements may be limiting during initial tumorigenesis. Therefore, the immunosurveillance of solid tumors may fail because they are ignored for too long by the immune system. However, these situations may prove promising for the induction of tumor-specific T cell immunity by vaccination, as the T cell repertoire against these antigens has a naïve phenotype and is not yet affected by tolerance mechanisms.
Similar content being viewed by others
References
Pardoll D (2001) T cells and tumours. Nature 411:1010
Dudley ME, Wunderlich JR, Robbins PF, et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850
Boon T, Coulie PG, Van den Eynde B (1997) Tumor antigens recognized by T cells. Immunol Today 18:267
Old LJ (1992) Tumor immunology: the first century. Curr Opin Immunol 4:603
Hengartner H, Odermatt B, Schneider R, et al (1988) Deletion of self-reactive T cells before entry into the thymus medulla. Nature 336:388
Mapara MY, Sykes M (2004) Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol 22:1136
Ochsenbein AF, Sierro S, Odermatt B, et al (2001) Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411:1058
Ochsenbein AF, Klenerman P, Karrer U, et al (1999) Immune surveillance against a peripheral solid tumor fails because of immunological ignorance. Proc Natl Acad Sci USA 96:2233
Bennett SR, Carbone FR, Karamalis F, et al (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393:478
Schoenberger SP, Toes RE, Voort EI van der, et al (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480
Ridge JP, Di Rosa F, Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474
Griffith TS, Brunner T, Fletcher SM, et al (1995) Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189
Burnet FM (1957) Cancer: a biological approach. Br Med J 1:779
Stutman O (1975) Immunodepression and malignancy. Adv Cancer Res 22:261
Newstead CG (1998) Assessment of risk of cancer after renal transplantation. Lancet 351:610
Kelly DM, Emre S, Guy SR, et al (1998) Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer 83:1237
Kuppers R (2003) B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol 3:801
Broek MF van den, Kägi D, Ossendorp F, et al (1996) Decreased tumor surveillance in perforin-deficient mice. J Exp Med 184:1781
Kägi D, Ledermann B, Bürki K, et al (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31
Smyth MJ, Thia KY, Cretney E, et al (1999) Perforin is a major contributor to NK cell control of tumor metastasis. J Immunol 162:6658
Smyth MJ, Thia KY, Street SE, et al (2000) Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 192:755
Shankaran V, Ikeda H, Bruce AT, et al (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107
Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329
Tureci O, Sahin U, Pfreundschuh M (1997) Serological analysis of human tumor antigens: molecular definition and implications. Mol Med Today 3:342
Stockert E, Jager E, Chen YT, et al (1998) A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp Med 187:1349
Disis ML, Calenoff E, McLaughlin G, et al (1994) Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 54:16
Jager E, Stockert E, Zidianakis Z, et al (1999) Humoral immune responses of cancer patients against “Cancer-Testis” antigen NY-ESO-1: correlation with clinical events. Int J Cancer 84:506
Houbiers JG, Burg SH van der, Watering LM van de, et al (1995) Antibodies against p53 are associated with poor prognosis of colorectal cancer. Br J Cancer 72:637
Houghton AN, Scheinberg DA (2000) Monoclonal antibody therapies-a ‘constant’ threat to cancer. Nat Med 6:373
Carter P (2001) Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1:118
Clynes R, Takechi Y, Moroi Y, et al (1998) Fc receptors are required in passive and active immunity to melanoma. Proc Natl Acad Sci USA 95:652
Clynes RA, Towers TL, Presta LG, et al (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443
Nakata M, Smyth MJ, Norihisa Y, et al (1990) Constitutive expression of pore-forming protein in peripheral blood gamma/delta T cells: implication for their cytotoxic role in vivo. J Exp Med 172:1877
Smyth MJ, Ortaldo JR, Shinkai Y, et al (1990) Interleukin 2 induction of pore-forming protein gene expression in human peripheral blood CD8+ T cells. J Exp Med 171:1269
Girardi M, Oppenheim DE, Steele CR, et al (2001) Regulation of cutaneous malignancy by gammadelta T cells. Science 294:605
Diefenbach A, Jensen ER, Jamieson AM, et al (2001) Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413:165
Natarajan K, Dimasi N, Wang J, et al (2002) Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu Rev Immunol 20:853
Street SE, Hayakawa Y, Zhan Y, et al (2004) Innate Immune surveillance of spontaneous B cell lymphomas by natural killer cells and λδ T cells. J Exp Med 199:879
Yee C, Thompson JA, Byrd D, et al (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA.99:16168
Hellstrom KE, Hellstrom I (1974) Lymphocyte-mediated cytotoxicity and blocking serum activity to tumor antigens. Adv Immunol 18:209
Qin Z, Richter G, Schuler T, et al (1998) B cells inhibit induction of T cell-dependent tumor immunity. Nat Med 4:627
Regnault A, Lankar D, Lacabanne V, et al (1999) Fcgamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J Exp Med 189:371
Dhodapkar KM, Krasovsky J, Williamson B, et al (2002) Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J Exp Med 195:125
Dyall R, Vasovic LV, Clynes RA, et al (1999) Cellular requirements for the monoclonal antibody-mediated eradication of an established solid tumor. Eur J Immunol 29:30
Mocikat R, Braumuller H, Gumy A, et al (2003) Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19:561
Valitutti S, Lanzavecchia A (1997) Serial triggering of TCRs: a basis for the sensitivity and specificity of antigen recognition. Immunol Today 18:299
Chambers CA, Allison JP (1997) Co-stimulation in T cell responses. Curr Opin Immunol 9:396
Schwartz RH (1990) A cell culture model for T lymphocyte clonal anergy. Science 248:1349
Chen L, Ashe S, Brady WA, et al (1992) Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71:1093
Watts TH, DeBenedette MA (1999) T cell co-stimulatory molecules other than CD28. Curr Opin Immunol 11:286
Croft M (2003) Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 3:609
Zinkernagel RM, Ehl S, Aichele P, et al (1997) Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity. Immunol Rev 156:199
Goodnow CC (1997) Chance encounters and organized rendezvous. Immunol Rev 156:5
Karrer U, Althage A, Odermatt B, et al (1997) 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 185:2157
Banks TA, Rouse BT, Kerley MK, et al (1995) Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol 155:1685
Futterer A, Mink K, Luz A, et al (1998) The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59
Lakkis FG, Arakelov A, Konieczny BT, et al (2000) Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 6:686
Chalasani G, Dai Z, Konieczny BT, et al (2002) Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci USA 99:6175
Kaech SM, Ahmed R (2001) Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat Immunol 2:415
Blattman JN, Cheng LE, Greenberg PD (2002) CD8(+) T cell responses: it’s all downhill after their prime. Nat Immunol 3:601
Zinkernagel RM, Hengartner H (2001) Regulation of the Immune Response by Antigen. Science 293:251
Moskophidis D, Lechner F, Pircher H, et al (1993) Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362:758
Ochsenbein AF, Zinkernagel RM (2000) Natural antibodies and complement link Innate and acquired immunity. Immunol Today 24:624
Machy P, Serre K, Leserman L (2000) Class I-restricted presentation of exogenous antigen acquired by Fcgamma receptor-mediated endocytosis is regulated in dendritic cells. Eur J Immunol 30:848
Kopf M, Abel B, Gallimore A, et al (2002) Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat Med 8:373
Ackerman AL, Cresswell P (2004) Cellular mechanisms governing cross-presentation of exogenous antigens. Nat Immunol 5:678
Heath WR, Carbone FR (2001) Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 19:47
Zinkernagel RM (2002) On cross-priming of MHC class I-specific CTL: rule or exception? Eur J Immunol 32:2385
Melief CJ (2003) Mini-review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming? Eur J Immunol 33:2645
Bevan MJ (1976) 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 143:1283
Bevan MJ (1987) Antigen recognition. Class discrimination in the world of immunology. Nature 325:192
Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86
Houde M, Bertholet S, Gagnon E, et al (2003) Phagosomes are competent organelles for antigen cross-presentation. Nature 425:402
Norbury CC, Chambers BJ, Prescott AR, et al (1997) Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells. Eur J Immunol 27:280
Rock KL (1996) A new foreign policy: MHC class I molecules monitor the outside world. Immunol Today 17:131
Schuurhuis DH, Ioan-Facsinay A, Nagelkerken B, et al (2002) Antigen-antibody immune complexes empower dendritic cells to efficiently prime specific CD8+ CTL responses in vivo. J Immunol 168:2240
Larsson M, Fonteneau JF, Somersan S, et al (2001) Efficiency of cross presentation of vaccinia virus-derived antigens by human dendritic cells. Eur J Immunol 31:3432
Sigal LJ, Crotty S, Andino R, et al (1999) Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen. Nature 398:77
Freigang S, Egger D, Bienz K, et al (2003) Endogenous neosynthesis vs. cross-presentation of viral antigens for cytotoxic T cell priming. Proc Natl Acad Sci USA 100:13477
Blattman JN, Antia R, Sourdive DJ, et al (2002) Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med 195:657
Nguyen LT, Elford AR, Murakami K, et al (2002) Tumor growth enhances cross-presentation leading to limited T cell activation without tolerance. J Exp Med 195:423
Kurts C, Miller JF, Subramaniam RM, et al (1998) Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J Exp Med 188:409
Huang AY, Golumbek P, Ahmadzadeh M, et al (1994) Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264:961
Bennett SR, Carbone FR, Karamalis F, et al (1997) Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J Exp Med 186:65
Kündig TM, Bachmann MF, DiPaolo C, et al (1995) Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science 268:1343
Wolkers MC, Stoetter G, Vyth-Dreese FA, et al (2001) Redundancy of direct priming and cross-priming in tumor-specific CD8+ T cell responses. J Immunol 167:3577
Ohashi PS, Oehen S, Buerki K, et al (1991) Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65:305
Spiotto MT, Yu P, Rowley DA, et al (2002) Increasing tumor antigen expression overcomes “ignorance” to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity 17:737
Wolkers MC, Brouwenstijn N, Bakker AH, et al (2004) Antigen bias in T cell cross-priming. Science 304:1314
Kurts C, Heath WR, Carbone FR, et al (1996) Constitutive class I-restricted exogenous presentation of self antigens in vivo. J Exp Med 184:923
Takahashi T, Sakaguchi S (2003) Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease. Curr Mol Med 3:693
Johnson A, France J, Sy MS, et al (1998) Down-regulation of the transporter for antigen presentation, proteasome subunits and MHC class I in tumor cell lines. Cancer Res 58:3660
Wagner WM, Ouyang Q, Pawelec G (2003) The abl/bcr gene product as a novel leukemia-specific antigen: peptides spanning the fusion region of abl/bcr can be recognized by both CD4+ and CD8+ T lymphocytes. Cancer Immunol Immunother 52:89
Ludewig B, Ochsenbein AF, Odermatt B, et al (2000) Immunotherapie with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease. J Exp Med 191:795
Dalyot-Herman N, Bathe OF, Malek TR (2000) Reversal of CD8+ T cell ignorance and induction of anti-tumor immunity by peptide-pulsed APC. J Immunol 165:6731
Perales MA, Blachere NE, Engelhorn ME, et al (2002) Strategies to overcome immune ignorance and tolerance. Semin Cancer Biol 12:63
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ochsenbein, A.F. Immunological ignorance of solid tumors. Springer Semin Immun 27, 19–35 (2005). https://doi.org/10.1007/s00281-004-0192-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-004-0192-0