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.
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.
authors.affiliation: National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. robbertvdm@gmail.com
authors.forename: Robbert G
authors.initials: RG
authors.lastname: van der Most
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Currie
authors.forename: Sathish
authors.initials: S
authors.lastname: Mahendran
authors.forename: Amy
authors.initials: A
authors.lastname: Prosser
authors.forename: Anna
authors.initials: A
authors.lastname: Darabi
authors.forename: Bruce W S
authors.initials: BW
authors.lastname: Robinson
authors.forename: Anna K
authors.initials: AK
authors.lastname: Nowak
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lake
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003520:Cyclophosphamide / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D060889:Inducible T-Cell Co-Stimulator Protein; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000276:immunology / Q000378:metabolism; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008654:Mesothelioma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D007166:Immunosuppressive Agents; D060889:Inducible T-Cell Co-Stimulator Protein; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D047889:Receptors, Tumor Necrosis Factor, Type II; D003841:Deoxycytidine; D019041:L-Selectin; D003520:Cyclophosphamide; D000093542:Gemcitabine