title: Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/αCD40 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 (αCD40) 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/αCD40 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/αCD40 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/αCD40. 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.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Subleski
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Tim
authors.initials: T
authors.lastname: Back
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick, MD 21702;
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, IL 60153;
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Watkins
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; and.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
authors.affiliation: Department of Dermatology, University of California, Davis, Sacramento, CA 95816.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702; wiltrour@mail.nih.gov.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D007376:Interleukin-2 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D019013:CD40 Antigens; C491899:Fas protein, mouse; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; C052617:Bcl2 protein, mouse