Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/αCD40 therapy

Jonathan M. Weiss, Jeff J. Subleski, Tim Back, Xin Chen, Stephanie K. Watkins, Hideo Yagita, Thomas J. Sayers, William J Murphy, Robert H. Wiltrout

Research output: Contribution to journalArticle

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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 tumorassociated Tregs and immature myeloid cells, including MDSCs. Tregs and MDSCs in the tumor microenvironment expressed active caspases after IL-2/aCD40 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/aCD40. 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.

Original languageEnglish (US)
Pages (from-to)5821-5829
Number of pages9
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - Jun 15 2014

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Tumor Microenvironment
Regulatory T-Lymphocytes
Interleukin-2
Cell Death
Therapeutics
Neoplasms
Fas Ligand Protein
Myeloid Cells
Immunotherapy
Myeloid-Derived Suppressor Cells
T-Lymphocytes
Adoptive Transfer
Immunosuppressive Agents
Caspases
Immunosuppression
Neutrophils
Leukocytes
Down-Regulation
Spleen
Apoptosis

ASJC Scopus subject areas

  • Immunology

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Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/αCD40 therapy. / Weiss, Jonathan M.; Subleski, Jeff J.; Back, Tim; Chen, Xin; Watkins, Stephanie K.; Yagita, Hideo; Sayers, Thomas J.; Murphy, William J; Wiltrout, Robert H.

In: Journal of Immunology, Vol. 192, No. 12, 15.06.2014, p. 5821-5829.

Research output: Contribution to journalArticle

Weiss, Jonathan M. ; Subleski, Jeff J. ; Back, Tim ; Chen, Xin ; Watkins, Stephanie K. ; Yagita, Hideo ; Sayers, Thomas J. ; Murphy, William J ; Wiltrout, Robert H. / Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/αCD40 therapy. In: Journal of Immunology. 2014 ; Vol. 192, No. 12. pp. 5821-5829.
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AU - Watkins, Stephanie K.

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