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.
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We thank R. Gault for assisting in the preparation of the manuscript and helpful discussions; K. Hunter for critically reviewing the manuscript. We thank W. Ma, M. Godfrey and D. Wilkins for technical assistance. W.J.M. thanks M. Bennett for guidance and suggestions over the years. This work was supported in part by R01 CA95572, R01 CA72669 and P20 RR16464 from the National Institutes of Health and with federal funds from the National Cancer Institute, US National Institutes of Health (under contract #N01-CO-12400).