ARID1A suppresses R-loop mediated STING-Type I Interferon pathway activation of anti-tumor immunity (RNA-Seq)

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. Overall design: RNA-seq of sgScramble and sgArid1a B16F10 tumors (in vivo); RNA-seq of sgScramble + PBS, sgArid1a + PBS, sgScramble + IFNg, and sgArid1a + IFNg treated B16F10 (in vitro); sgScramble, sgArid1a, Cgas dKO, Sting dKO, and sgArid1a + anti-IFNAR B16F10 (in vitro); DMSO treated B16F10, BD98 treated B16F10, BD98 + anti-IFNAR treated B16F10 (in vitro); sgScramble + DMSO, sgArid1a + DMSO, sgArid1a + ruxilitinib (JAK1/2i) B16F10 cells (in vitro); RNA-seq of sgArid1a and sgScramble MC38 cell lines (in vitro); RNA-seq of Arid1a -/- or WT MEF cells (in vitro); Total-RNA-seq of sgArid1a or sgScramble B16F10 cells (in vitro).