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

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

doi:10.1016/j.cell.2024.04.025

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

Cell. 2024 May 9:S0092-8674(24)00451-3. doi: 10.1016/j.cell.2024.04.025. Online ahead of print.

Authors

Matthew B Maxwell¹, Marianne S Hom-Tedla², Jawoon Yi³, Shitian Li¹, Samuel A Rivera¹, Jingting Yu⁴, Mannix J Burns³, Helen M McRae³, Braden T Stevenson³, Katherine E Coakley², Josephine Ho³, Kameneff Bojorquez Gastelum³, Joshua C Bell³, Alexander C Jones³, Ramez N Eskander⁵, Emily C Dykhuizen⁶, Gerald S Shadel⁷, Susan M Kaech⁸, Diana C Hargreaves⁹

Affiliations

¹ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92092, USA; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
² Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Gynecologic Oncology, University of California, San Diego, San Diego, CA, USA.
³ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁴ Integrative Genomics and Bioinformatics Core, Salk Institute of Biological Studies, La Jolla, CA 92037, USA.
⁵ Center for Personalized Cancer Therapy and Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, UC San Diego Moores Cancer Center, La Jolla, CA, USA.
⁶ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
⁷ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁸ NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁹ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: dhargreaves@salk.edu.

PMID: 38754421
DOI: 10.1016/j.cell.2024.04.025

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.