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. 2009 Aug;58(8):1219-28. doi: 10.1007/s00262-008-0628-9. Epub 2008 Dec 4.

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-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cyclophosphamide / therapeutic use*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Immunosuppressive Agents / therapeutic use*
  • Inducible T-Cell Co-Stimulator Protein
  • Kaplan-Meier Estimate
  • Ki-67 Antigen / immunology
  • Ki-67 Antigen / metabolism
  • L-Selectin / immunology
  • L-Selectin / metabolism
  • Lymphocyte Depletion*
  • Mesothelioma / drug therapy*
  • Mesothelioma / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Receptors, Tumor Necrosis Factor, Type II / immunology*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • Icos protein, mouse
  • Immunosuppressive Agents
  • Inducible T-Cell Co-Stimulator Protein
  • Ki-67 Antigen
  • Mki67 protein, mouse
  • Receptors, Tumor Necrosis Factor, Type II
  • Deoxycytidine
  • L-Selectin
  • Cyclophosphamide
  • gemcitabine