Abstract
Models for immune-mediated tumor regression in mice have defined an essential role for cytotoxic T lymphocytes (CTLs); however, naturally occurring tumor immunity in humans is poorly understood 1 . Patients with paraneoplastic cerebellar degeneration (PCD) provide an opportunity to explore the mechanisms underlying tumor immunity to breast and ovarian cancer. Although tumor immunity and autoimmune neuronal degeneration in PCD correlates with a specific antibody response to the tumor and brain antigen cdr2 2, 3 , this humoral response has not been shown to be pathogenic 3, 4 . Here we present evidence for a specific cellular immune response in PCD patients. We have detected expanded populations of MHC class I-restricted cdr2-specific CTLs in the blood of 3/3 HLA-A2.1 + PCD patients, providing the first description, to our knowledge, of tumor-specific CTLs using primary human cells in a simple recall assay. Cross-presentation of apoptotic cells by dendritic cells also led to a potent CTL response. These results indicate a model whereby immature dendritic cells that engulf apoptotic tumor cells can mature and migrate to draining lymph organs where they could induce a CTL response to tissue-restricted antigens. In PCD, peripheral activation of cdr2-specific CTLs is likely to contribute to the subsequent development of the autoimmune neuronal degeneration.
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References
Schuler, G. & Steinman, R.M. Dendritic cells as adjuvants for immune-mediated resistance to tumors. J. Exp. Med. 186, 1183–1187 (1997).
Boon, T. & Old, L.J. Cancer tumor antigens. Curr. Opin. Immunol. 9, 681–683 (1997).
Darnell, R.B. Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity and the brain. Proc. Natl. Acad. Sci. USA 93, 4529–4536 (1996).
Furneaux, H.L., Reich, L. & Posner, J.P. Autoantibody synthesis in the central nervous system of patients with paraneoplastic syndromes. Neurology 40 , 1085–1091 (1990).
Dropcho, E., Chen, Y., Posner, J. & Old, L. Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. Proc. Natl. Acad. Sci. USA 84, 1–5 (1987).
Fathallah-Shaykh, H., Wolf, S., Wong, E., Posner, J. & Furneaux, H. Cloning of a leucine-zipper protein recognized by the sera of patients with antibody-associated paraneoplastic cerebellar degeneration. Proc. Natl. Acad. Sci. USA 88, 3451– 3454 (1991).
Sakai, K., Mitchell, D.J., Tsukamoto, T. & Steinman, L. Isolation of a complementary DNA clone encoding an autoantigen recognized by an anti-neuronal antibody from a patient with paraneoplastic cerebellar degeneration. Ann. Neurol. 28, 692– 698 (1990).
Corradi, J.P., Yang, C.W., Darnell, J.C., Dalmau, J. & Darnell, R.B. A post-transcriptional regulatory mechanism restricts expression of the paraneoplastic cerebellar degeneration antigen cdr2 to immune privileged tissues. J. Neurosci. 17, 1406–1415 (1997).
Peterson, K., Rosenblum, M.K., Kotanides, H. & Posner, J.B. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 42, 1931–1937 (1992).
Bender, A., Sapp, M., Schuler, G., Steinman, R.M. & Bhardwaj, N. Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J. Immunol. Methods 196, 121–135 ( 1996).
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).
Bennett, S.R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–80 (1998).
Boon, T., Cerottini, J.C., Van den Eynde, B., van der Bruggen, P. & Van Pel, A. Tumor antigens recognized by T lymphocytes. Ann. Rev. Immunol. 12, 337–365 (1994).
Carmichael, A., Jin, X., Sissons, P. & Borysiewicz, L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV- 1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein- Barr virus in late disease. J. Exp. Med. 177, 249–56 (1993).
Koup, R.A. et al. Limiting dilution analysis of cytotoxic T lymphocytes to human immunodeficiency virus gag antigens in infected persons: in vitro quantitation of effector cell populations with p17 and p24 specificities. J. Exp. Med. 174, 1593–1600 (1991).
McMichael, A. Cytotoxic T lymphocytes specific for influenza virus. Curr. Top. Microbiol. Immunol. 189, 75–91 (1994).
Darnell, R.B. & DeAngelis, L.M. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 341, 21–22 ( 1993).
Devita, V.T., Hellman, S. & Rosenberg, S. in Cancer, Principles and Practice of Oncology, 1930–1931 (J.B. Lippincott, Philadelphia, 1989).
Huang, A.Y. et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–5 (1994).
Zitvogel, L. et al. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J. Exp. Med. 183, 87– 97 (1996).
Dalmau, J. et al. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 75, 99–109 (1995).
Strand, S. et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells—a mechanism of immune evasion? Nature Med. 2, 1361-1366 (1996).
Corriveau, R.A., Huh, G.S. & Shatz, C.J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 1–20 (1998).
Bhardwaj, N. et al. Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells. J. Clin. Invest. 94, 797–807 (1994).
Barouch, D. et al. HLA-A2 subtypes are functionally distinct in peptide binding and presentation. J. Exp. Med. 182, 1847 –56 (1995).
Acknowledgements
We thank the staff of the Rockefeller Hospital GCRC, particularly M. McNiff and M. Keogh, for facilitating the patient studies. We thank E. Albert for help in patient recruitment. We thank R. Steinman, E. Gotschlich and members of our laboratories for discussions and review of the manusript. Support from the Department of Defense (Breast Cancer Research Award #DAMD017-94-J-4277), the National Multiple Sclerosis Society (PP0507), and the NIH Medical Scientist Training Program grant (GM-07739) is acknowledged. Clinical work at the RU Hospital GCRC was supported through grant M01 RR00102, and approved by institutional IRB #RDA-148. N.B. was supported by NIH grant AI-39516 and grants from the SLE Foundation.
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Albert, M., Darnell, J., Bender, A. et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration . Nat Med 4, 1321–1324 (1998). https://doi.org/10.1038/3315
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DOI: https://doi.org/10.1038/3315
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