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

• Published in: Cancer Immunology, Immunotherapy Vol. 58; no. 8; pp. 1219 - 1228
• Main Authors: van der Most, Robbert G, Currie, Andrew J, Mahendran, Sathish, Prosser, Amy, Darabi, Anna, Robinson, Bruce W. S, Nowak, Anna K, Lake, Richard A
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.08.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Adoptive Transfer; Animals; Antibodies; Antigens, Differentiation, T-Lymphocyte - immunology; Antigens, Differentiation, T-Lymphocyte - metabolism; Antineoplastic agents; Biological and medical sciences; Cancer and Oncology; Cancer och onkologi; Cancer Research; Cancer therapies; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cells; Chemotherapy; Clinical Medicine; Cyclophosphamide; Cyclophosphamide - therapeutic use; Cytotoxicity; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Gemcitabine; Immune system; Immunology; Immunosuppressive Agents - therapeutic use; Immunotherapy; Inducible T-Cell Co-Stimulator Protein; Kaplan-Meier Estimate; Ki-67 Antigen - immunology; Ki-67 Antigen - metabolism; Klinisk medicin; L-Selectin - immunology; L-Selectin - metabolism; Lymphocyte Depletion; Lymphocytes; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - immunology; Mice; Mice, Inbred BALB C; Mice, Nude; Oncology; Original; Original Article; Pharmacology. Drug treatments; Receptors, Tumor Necrosis Factor, Type II - immunology; Receptors, Tumor Necrosis Factor, Type II - metabolism; Regulatory CD4(+) T cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Tumor immunity; Tumors; Chemotherapy; Cyclophosphamide; Tumor immunity; Gemcitabine; Regulatory CD4; Mesothelioma; T cells; Antineoplastic agent; Effectory cell; CD4 T lymphocyte; Concurrent; Eradication; Efficiency; Immunotherapy; T-Lymphocyte; Pyrimidine nucleoside; Regulatory cell; Immune response; Malignant tumor; Gene expression; Tumor necrosis factor receptor 2; Alkylating agent; Oxazaphosphinane derivatives; Treatment; Depletion; Antimetabolic; Nitrogen mustard; Pyrimidine derivatives; Suppressive cell; Fluorine Organic compounds; Cancer
• DOI: 10.1007/s00262-008-0628-9
• ISSN: 0340-7004; 1432-0851

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.