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

Nature Medicine volume 13, pages 354–360 (2007)Cite this article

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.

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Figure 1: Both CD4+ and CD8+ cells acquire a memory phenotype after treatment with CD40 antibody and IL-2 but only the CD8+ cell population increases.
Figure 2: Both CD4+ and CD8+ cells enter the cell cycle after treatment with CD40 antibody and IL-2.
Figure 3: Administration of CD40 antibody and IL-2, CD40 antibody and IL-15, or CpG and IL-12 induce elevated CD4+ T-cell apoptosis.
Figure 4: Treatment with CD40 antibody and IL-2 stimulates CD4+ T-cell expansion in the absence of IFN-γ or IFN-γ receptor.
Figure 5: CD40 antibody and IL-2 combination therapy improves primary survival in intravenous tumor models, but decreases secondary responses.
Figure 6: IFN-γ responsiveness by host cells reduces the effectiveness of tumor vaccination following CD40 antibody and IL-2 combination therapy.

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Acknowledgements

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).

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  1. Vanessa Berner and Haiyan Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Nevada at Reno, Reno, 89557, Nevada, USA

    Vanessa Berner, Haiyan Liu, Qing Zhou, Kory L Alderson, Kai Sun, Lisbeth A Welniak & William J Murphy

  2. Department of Physiology & Cell Biology, University of Nevada at Reno, Reno, 89557, Nevada, USA

    Doug Redelman

  3. Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, 21702, Maryland, USA

    Jonathan M Weiss, Timothy C Back & Robert H Wiltrout

  4. National Institute on Aging, Baltimore, 21224, Maryland, USA

    Dan L Longo

  5. Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Bruce R Blazar

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Contributions

R.H.W., D.L.L., L.A.W., D.R., B.R.B. and W.J.M. oversaw experiments, conducted data analysis and assisted in the writing of the manuscript. J.M.W. and T.C.B. conducted the Ifngr−/− experiments. K.L.A., K.S., V.B., H.L. and Q.Z. conducted all other experiments and assisted in the writing of the manuscript.

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Correspondence to William J Murphy.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expansion of CD8+ cells in lymph nodes and peripheral blood immediately after treatment with anti-CD40/IL-2 and sustained memory phenotype at day 42. (PDF 48 kb)

Supplementary Fig. 2

Comparison of apoptosis induction in the T cells of mice treated with CpG/IL-12 compared to CpGs alone or to IL-2/IL-12 administration. (PDF 87 kb)

Supplementary Fig. 3

Treatment schema for the evaluation of primary and secondary tumor responses. (PDF 67 kb)

Supplementary Fig. 4

Treatment schema for the evaluation of a clinically relevant tumor response. (PDF 53 kb)

Supplementary Methods (PDF 57 kb)

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Berner, V., Liu, H., Zhou, Q. et al. IFN-γ mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy. Nat Med 13, 354–360 (2007). https://doi.org/10.1038/nm1554

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