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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• ARID1A mutations are linked to favorable responses to immune checkpoint blockade (ICB) across various solid tumors.
• The underlying mechanisms driving this improved ICB sensitivity in ARID1A-mutant cancers remain largely undefined.

Purpose of the Study:

• To elucidate the molecular mechanisms by which ARID1A loss influences anti-tumor immunity and ICB response.
• To investigate the role of interferon signaling and DNA sensing pathways in ARID1A-deficient tumors.

Main Methods:

• Utilized murine cancer models with ARID1A loss to assess immune phenotypes and gene expression.
• Analyzed interferon (IFN) gene signatures, R-loop formation, and cytosolic single-stranded DNA (ssDNA) accumulation.
• Investigated the involvement of RNASEH2B, TREX1, and STING-dependent type I IFN signaling.

Main Results:

• ARID1A loss induced anti-tumor immunity, including increased CD8+ T cell infiltration and cytolytic activity in murine models.
• ARID1A-deficient cancers exhibited an ARID1A-IFN signature linked to R-loops and cytosolic ssDNA.
• Resolving R-loops or degrading cytosolic ssDNA abrogated the ARID1A-IFN signature.
• STING-dependent type I IFN signaling mediated the ARID1A-IFN signature and anti-tumor immunity, crucial for ICB response.

Conclusions:

• ARID1A loss triggers anti-tumor immunity via a STING-dependent type I IFN pathway, driven by R-loops and cytosolic ssDNA.
• This pathway is essential for the enhanced responsiveness of ARID1A-mutant tumors to ICB treatment.
• Defines a molecular basis for improved ICB efficacy in ARID1A-mutant cancers.