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Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy

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Abstract

Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67hi) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67hi CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.

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Acknowledgments

This work was supported in part by the National Health and Medical Research Council of Australia.

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  1. Robbert G. van der Most

    Present address: GlaxoSmithKline Biologicals, 89 Rue de l’Institut, 1300, Rixensart, Belgium

Authors and Affiliations

  1. National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia

    Robbert G. van der Most, Andrew J. Currie, Sathish Mahendran, Amy Prosser, Bruce W. S. Robinson, Anna K. Nowak & Richard A. Lake

  2. Glioma Immunotherapy Group, University of Lund, Lund, Sweden

    Anna Darabi

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  1. Robbert G. van der Most
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Correspondence to Robbert G. van der Most.

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van der Most, R.G., Currie, A.J., Mahendran, S. et al. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother 58, 1219–1228 (2009). https://doi.org/10.1007/s00262-008-0628-9

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