Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/alphaCD40 therapy Journal Article

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Authors: Weiss, J. M.; Subleski, J. J.; Back, T.; Chen, X; Watkins, S. K.; Yagita, H.; Sayers, T. J.; Murphy, W. J.; Wiltrout, R. H.
Article Title: Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/alphaCD40 therapy
Abstract: Fas ligand expression in certain tumors has been proposed to contribute to immunosuppression and poor prognosis. However, immunotherapeutic approaches may elicit the Fas-mediated elimination of immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within tumors that represent major obstacles for cancer immunotherapy. Previously, we showed that IL-2 and agonistic CD40 Ab (alphaCD40) elicited synergistic antitumor responses coincident with the efficient removal of Tregs and MDSCs. We demonstrate in this study in two murine tumor models that Treg and MDSC loss within the tumor microenvironment after IL-2/alphaCD40 occurs through a Fas-dependent cell death pathway. Among tumor-infiltrating leukocytes, CD8(+) T cells, neutrophils, and immature myeloid cells expressed Fas ligand after treatment. Fas was expressed by tumor-associated Tregs and immature myeloid cells, including MDSCs. Tregs and MDSCs in the tumor microenvironment expressed active caspases after IL-2/alphaCD40 therapy and, in contrast with effector T cells, Tregs significantly downregulated Bcl-2 expression. In contrast, Tregs and MDSCs proliferated and expanded in the spleen after treatment. Adoptive transfer of Fas-deficient Tregs or MDSCs into wild-type, Treg-, or MDSC-depleted hosts resulted in the persistence of Tregs or MDSCs and the loss of antitumor efficacy in response to IL-2/alphaCD40. These results demonstrate the importance of Fas-mediated Treg/MDSC removal for successful antitumor immunotherapy. Our results suggest that immunotherapeutic strategies that include exploiting Treg and MDSC susceptibility to Fas-mediated apoptosis hold promise for treatment of cancer.
Journal Title: Journal of Immunology
Volume: 192
Issue: 12
ISSN: 1550-6606
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: 5821
End Page: 5829
Language: eng
DOI/URL:

10.4049/jimmunol.1400404
Notes: LR: 20150325; GR: Z01 BC009262-25/Intramural NIH HHS/United States; GR: Z99 CA999999/Intramural NIH HHS/United States; JID: 2985117R; 0 (Antigens, CD40); 0 (Antigens, CD95); 0 (Antineoplastic Agents); 0 (Fas protein, mouse); 0 (Interleukin-2); 0 (Proto-Oncogene Proteins c-bcl-2); 114100-40-2 (Bcl2 protein, mouse); NIHMS587922; OID: NLM: NIHMS587922; OID: NLM: PMC4048774; 2014/05/07 [aheadofprint]; ppublish