IFN-γ mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy

Vanessa Berner, Haiyan Liu, Qing Zhou, Kory L. Alderson, Kai Sun, Jonathan M. Weiss, Timothy C. Back, Dan L. Longo, Bruce R. Blazar, Robert H. Wiltrout, Lisbeth A. Welniak, Doug Redelman, William J Murphy

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Protective cell-mediated immune responses in cancer are critically dependent on T-helper type 1 (TH1) cytokines such as interferon-γ (IFN-γ). We have previously shown that the combination of CD40 stimulation and interleukin-2 (IL-2) leads to synergistic antitumor responses in several models of advanced metastatic disease. We now report that after this treatment and other immunotherapy regimens, the CD4+ T-cell population, in contrast to CD8+ T cells, did not significantly increase but rather exhibited a substantial level of apoptosis that was dependent on IFN-γ. Mice immunized with tumor cells and treated with an immunotherapy regimen that was initially protective were later unable to mount effective memory responses compared with immunized mice not receiving immunotherapy. Immunotherapy given to tumor-bearing Ifngr-/- mice resulted in restoration of secondary responses. Thus, although immunotherapeutic regimens inducing strong IFN-γ responses can lead to successful early antitumor efficacy, they may also impair the development of durable antitumor responses.

Original languageEnglish (US)
Pages (from-to)354-360
Number of pages7
JournalNature Medicine
Volume13
Issue number3
DOIs
StatePublished - Mar 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Berner, V., Liu, H., Zhou, Q., Alderson, K. L., Sun, K., Weiss, J. M., Back, T. C., Longo, D. L., Blazar, B. R., Wiltrout, R. H., Welniak, L. A., Redelman, D., & Murphy, W. J. (2007). IFN-γ mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy. Nature Medicine, 13(3), 354-360. https://doi.org/10.1038/nm1554