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Supplemental Figure Legends 1-5 from TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors

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posted on 2023-04-03, 23:28 authored by Brian J. Francica, Ali Ghasemzadeh, Anthony L. Desbien, Debebe Theodros, Kelsey E. Sivick, Gabrielle L. Reiner, Laura Hix Glickman, Ariel E. Marciscano, Andrew B. Sharabi, Meredith L. Leong, Sarah M. McWhirter, Thomas W. Dubensky, Drew M. Pardoll, Charles G. Drake

S1: Timeline of necrosis after CDN injection. S2: CDN injection causes a distinct cytokine and cellular profile in the tumor draining lymph nodes. S3: B16F10 is not directly killed by CDN exposure and behaves similarly to other mouse and human cell lines. S4: TNFα blockade reduces necrosis after IT CDN. S5: Outgrowth and CDN treatment of B16F10 is effected in selected knockout animals.

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NIH

NCI

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Patrick C. Walsh Fund

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ARTICLE 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 critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422–33. ©2018 AACR.

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    Cancer Immunology Research

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    ImmunologyCytokinesImmunotherapyCancer vaccinesSkin Cancers

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