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- Title
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.
- Authors
Most, Robbert G.; Currie, Andrew J.; Mahendran, Sathish; Prosser, Amy; Darabi, Anna; Robinson, Bruce W. S.; Nowak, Anna K.; Lake, Richard A.
- 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.
- Subjects
T cells; CELL death; IMMUNE system; DRUG therapy; IMMUNOSUPPRESSION; MESOTHELIOMA
- Publication
Cancer Immunology, Immunotherapy, 2009, Vol 58, Issue 8, p1219
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-008-0628-9