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. 2024 Jun 20;187(13):3390-3408.e19.
doi: 10.1016/j.cell.2024.04.025. Epub 2024 May 15.

ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity

Matthew B Maxwell  1 , Marianne S Hom-Tedla  2 , Jawoon Yi  3 , Shitian Li  1 , Samuel A Rivera  1 , Jingting Yu  4 , Mannix J Burns  3 , Helen M McRae  3 , Braden T Stevenson  3 , Katherine E Coakley  2 , Josephine Ho  3 , Kameneff Bojorquez Gastelum  3 , Joshua C Bell  3 , Alexander C Jones  3 , Ramez N Eskander  5 , Emily C Dykhuizen  6 , Gerald S Shadel  7 , Susan M Kaech  8 , Diana C Hargreaves  9
Affiliations

ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity

Matthew B Maxwell et al. Cell. .

Abstract

Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.

Keywords: ARID1A; R-loops; STING; SWI/SNF complex; anti-tumor immunity; cancer immunotherapy; cytosolic DNA; type I IFN.

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Conflict of interest statement

Declaration of interests S.M.K. is on the scientific advisory boards and has equity in EvolveImmune Therapeutics, Affini-T Therapeutics, Arvinas, Pfizer, and the Barer Institute, Inc.

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