Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Tumor-specific killer cells in paraneoplastic cerebellar degeneration

Nature Medicine volume 4, pages 1321–1324 (1998)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Western blot analysis of serum and CSF immunoreactivity to cdr2.
Figure 2: Peripheral blood of PCD patients contains cdr2-specific killer cells.
Figure 3: Enhanced CTL activity is detected when apoptotic HeLa cells are the source of cdr2 epitopes.

Similar content being viewed by others

References

  1. Schuler, G. & Steinman, R.M. Dendritic cells as adjuvants for immune-mediated resistance to tumors. J. Exp. Med. 186, 1183–1187 (1997).

    Article  CAS  Google Scholar 

  2. Boon, T. & Old, L.J. Cancer tumor antigens. Curr. Opin. Immunol. 9, 681–683 (1997).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. 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).

    Article  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. Bennett, S.R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–80 (1998).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. McMichael, A. Cytotoxic T lymphocytes specific for influenza virus. Curr. Top. Microbiol. Immunol. 189, 75–91 (1994).

    CAS  PubMed  Google Scholar 

  17. Darnell, R.B. & DeAngelis, L.M. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 341, 21–22 ( 1993).

    Article  CAS  Google Scholar 

  18. Devita, V.T., Hellman, S. & Rosenberg, S. in Cancer, Principles and Practice of Oncology, 1930–1931 (J.B. Lippincott, Philadelphia, 1989).

    Google Scholar 

  19. Huang, A.Y. et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–5 (1994).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. 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).

    Article  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Barouch, D. et al. HLA-A2 subtypes are functionally distinct in peptide binding and presentation. J. Exp. Med. 182, 1847 –56 (1995).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neuro-Oncology, Rockefeller University, 1230 York Avenue, New York, 10021-6399, New York, USA

    Matthew L. Albert, Jennifer C. Darnell & Robert B. Darnell

  2. Laboratory of Cellular Physiology and Immunology, Rockefeller University, 1230 York Avenue, New York, 10021-6399, New York, USA

    Matthew L. Albert, Armin Bender, Loise M. Francisco & Nina Bhardwaj

Authors
  1. Matthew L. Albert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer C. Darnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Armin Bender
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Loise M. Francisco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nina Bhardwaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert B. Darnell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert B. Darnell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/3315

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing