Abstract
Tumor antigen-specific T-cell tolerance limits the efficacy of therapeutic cancer vaccines. Antigen-presenting cells mediate the induction of T-cell tolerance to self-antigens. We therefore assessed the fate of tumor-specific CD4+ T cells in tumor-bearing recipients after in vivo activation of antigen-presenting cells with antibodies against CD40. Such treatment not only preserved the responsiveness of this population, but resulted in their endogenous activation. Established tumors regressed in vaccinated mice treated with antibody against CD40 at a time when no response was achieved with vaccination alone. These results indicate that modulation of antigen-presenting cells may be a useful strategy for enhancing responsiveness to immunization.
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References
Hung, K. et al. The central role of CD4(+) T cells in the antitumor immune response. J. Exp. Med. 188, 2357– 2368 (1998).
Topalian, S.L. MHC class II restricted tumor antigens and the role of CD4+ T cells in cancer immunotherapy. Curr. Opin. Immunol. 6, 741–745 (1994).
Keene, J.A. & Forman, J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155, 768–782 (1982).
Kalams, S.A. & Walker, B.D. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J. Exp. Med. 188, 2199–2204 (1998).
Levitsky, H.I., Lazenby, A., Hayashi, R.J. & Pardoll, D.M. In vivo priming of two distinct antitumor effector populations: the role of MHC class I expression. J. Exp. Med. 179, 1215–1224 (1994).
Staveley-O' Carroll, K. et al. Induction of antigen-specific T cell anergy: An early event in the course of tumor progression. Proc. Natl. Acad. Sci. USA 95, 1178–1183 (1998).
Sotomayor, E.M., Borrello, I. & Levitsky, H.I. Tolerance and cancer: a critical issue in tumor immunology. Crit. Rev. Oncog. 7, 433– 456 (1996).
Heath, W.R., Kurts, C., Miller, J.F. & Carbone, F.R. Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens. J. Exp. Med. 187, 1549–1553 (1998).
Grewal, I.S. & Flavell, R.A. A central role of CD40 ligand in the regulation of CD4+ T-cell responses. Immunol. Today 17, 410–414 (1996).
Noelle, R.J. CD40 and its ligand in host defense. Immunity 4, 415–419 (1996).
Kirberg, J. et al. Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J. Exp. Med. 180, 25–34 (1994).
Rolink, A., Melchers, F. & Andersson, J. The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching. Immunity 5, 319–330 (1996).
Constant, S. et al. Are primed CD4+ T lymphocytes different from unprimed cells? Eur. J. Immunol. 24, 1073– 1079 (1994).
Braesch-Andersen, S. et al. Biochemical characteristics and partial amino acid sequence of the receptor-like human B cell and carcinoma antigen CDw40. J. Immunol. 142, 562–567 (1989).
Stamenkovic, I., Clark, E.A. & Seed, B. A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. EMBO J. 8, 1403–1410 (1989).
van den Oord, J.J. et al. CD40 is a prognostic marker in primary cutaneous malignant melanoma. Am. J. Pathol. 149, 1953– 1961 (1996).
Pammer, J., Weninger, W., Mazal, P.R., Horvat, R. & Tschachler, E. Expression of the CD40 antigen on normal endothelial cells and in benign and malignant tumours of vascular origin. Histopathology 29, 517– 524 (1996).
Viac, J., Schmitt, D. & Claudy, A. CD40 expression in epidermal tumors. Anticancer Res. 17, 569–572 (1997).
Kluth, B. et al. Endothelial expression of CD40 in renal cell carcinoma. Cancer Res. 57, 891–899 (1997).
Jakobson, E., Jonsson, G., Bjorck, P. & Paulie, S. Stimulation of CD40 in human bladder carcinoma cells inhibits anti- Fas/APO-1 (CD95)-induced apoptosis. Int. J. Cancer 77, 849– 853 (1998).
Kearney, E.R., Pape, K.A., Loh, D.Y. & Jenkins, M.K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327– 339 (1994).
Pape, K.A., Merica, R., Mondino, A., Khoruts, A. & Jenkins, M.K. Direct evidence that functionally impaired CD4+ T cells persist in vivo following induction of peripheral tolerance. J. Immunol. 160, 4719– 4729 (1998).
Kurts, C., Kosaka, H., Carbone, F.R., Miller, J.F. & Heath, W.R. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells. J. Exp. Med. 186, 239– 245 (1997).
Kurts, C. et al. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J. Exp. Med. 184, 923–930 (1996).
Adler, A.J. et al. CD4(+) T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells. J. Exp. Med. 187, 1555–1564 (1998).
Lanzavecchia, A. Immunology. Licence to kill. Nature 393, 413–414 (1998).
Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Albert, M.L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I- restricted CTLs. Nature 392, 86–89 (1998).
Inaba, K. et al. High levels of a major histocompatibility complex II-self peptide complex on dendritic cells from the T cell areas of lymph nodes. J. Exp. Med. 186, 665–672 (1997).
Fuchs, E.J. & Matzinger, P. Is cancer dangerous to the immune system? Semin. Immunol. 8, 271– 280 (1996).
Medzhitov, R. & Janeway, C.A., Jr. Innate immune recognition and control of adaptive immune responses. Semin. Immunol. 10, 351–353 (1998).
Janeway, C.A., Jr. How the immune system recognizes invaders. Sci. Am. 269, 72–79 (1993).
Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).
Ridge, J.P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T- helper and a T-killer cell. Nature 393, 474–478 (1998).
Schoenberger, S.P., Toes, R.E., van der Voort, E.I., Offringa, R. & Melief, C.J. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393, 480–483 (1998).
Bennett, S.R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).
Guerder, S. & Matzinger, P. Activation versus tolerance: a decision made by T helper cells. Cold Spring Harb. Symp. Quant. Biol. 54, 799–805 (1989).
Kurts, C. et al. CD4+ T cell help impairs CD8+ T cell deletion induced by cross- presentation of self-antigens and favors autoimmunity. J. Exp. Med. 186, 2057–2062 (1997).
Lane, P., Haller, C. & McConnell, F. Evidence that induction of tolerance in vivo involves active signaling via a B7 ligand-dependent mechanism: CTLA4-Ig protects V beta 8+ T cells from tolerance induction by the superantigen staphylococcal enterotoxin B. Eur. J. Immunol. 26, 858– 862 (1996).
Van Parijs, L., Ibraghimov, A. & Abbas, A.K. The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity 4, 321–328 (1996).
Lanoue, A., Bona, C., von Boehmer, H. & Sarukhan, A. Conditions that induce tolerance in mature CD4+ T cells. J. Exp. Med. 185, 405–414 (1997).
Bogen, B. Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma. Eur. J. Immunol. 26, 2671– 2679 (1996).
Lo, D. et al. Peripheral tolerance to an islet cell-specific hemagglutinin transgene affects both CD4+ and CD8+ T cells. Eur. J. Immunol. 22, 1013–1022 (1992).
Verhasselt, V. et al. Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cells: evidence for a soluble CD14-dependent pathway. J. Immunol. 158, 2919–2925 (1997).
Bowen, F., Haluskey, J. & Quill, H. Altered CD40 ligand induction in tolerant T lymphocytes. Eur. J. Immunol. 25, 2830– 2834 (1995).
Ferlin, W.G. et al. The induction of a protective response in Leishmania major-infected BALB/c mice with anti-CD40 mAb. Eur. J. Immunol. 28, 525–531 (1998).
Dullforce, P., Sutton, D.C. & Heath, A.W. Enhancement of T cell-independent immune responses in vivo by CD40 antibodies. Nature Med. 4, 88–91 (1998).
Morgan, D.J. et al. Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity. J. Immunol. 160, 643–651 (1998).
Acknowledgements
The authors thank S. Cooke for technical assistance, and D. Pardoll, A. Adler and E. Fuchs for discussions and review of the manuscript. This work was supported by a gift from the Hanford family, and by PHS grants RO1 CA78658 and CA078656. E.M.S. is a Fellow of the Lymphoma Research Foundation of America. I.B. is a Fellow of the Leukemia Society of America and H.I.L. is a Scholar of the Leukemia Society of America.
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Sotomayor, E., Borrello, I., Tubb, E. et al. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med 5, 780–787 (1999). https://doi.org/10.1038/10503
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DOI: https://doi.org/10.1038/10503
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