TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors.

Cancer Immunology Research
Brian J FrancicaCharles G Drake

Abstract

The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove c...Continue Reading

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Citations

Jul 17, 2018·Immunotherapy·Jeremy B Foote, Leisha A Emens
May 1, 2019·Journal for Immunotherapy of Cancer·Weiqing JingMichael B Dwinell
Aug 11, 2020·Oncotarget·Brandon Yi Da HoongEe Sin Chen
Aug 18, 2020·Cellular & Molecular Immunology·Yuan SongHaiyan Liu
Mar 22, 2020·Science Immunology·Christopher J NicolaiDavid H Raulet
Aug 23, 2020·Vaccines·Himanshu GogoiLei Jin
Sep 2, 2018·Molecular and Cellular Pediatrics·Stefan E G BurdachKlaus-Michael Debatin
Mar 13, 2020·Nature Reviews. Cancer·Martin McLaughlinKevin J Harrington
Nov 11, 2020·Molecular Cell·Lauren J LaheyLingyin Li
Jul 16, 2020·Immunity·Sarah M McWhirter, Caroline A Jefferies
Jun 3, 2021·Cancers·Afsaneh AmouzegarJason J Luke
May 18, 2021·Frontiers in Immunology·Kari A ShaverAlicja J Copik
Aug 4, 2021·Journal for Immunotherapy of Cancer·Casey R AgerMichael A Curran
Jun 26, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zhe TangTimothy C Thompson

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