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EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

ABSTRACT: Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are characterized by worse overall outcomes and resistance to immunotherapy. Here, we identified a molecular mechanism by which KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY producing a BRCAness phenotype characterized by HRR defects and sensitivity to PARP inhibitors (PARPis). Defective HRR increases genomic instability leading to high tumor mutational burden (TMB), which prompts an innate immune response. Notably, EMSY accumulation also suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling, impairing the growth of KEAP1-mutant tumors. Our results suggest that targeting the PARP and STING pathways, individually or in combination, represent a novel therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

ORGANISM(S): Mus musculus

PROVIDER: GSE178503 | GEO | 2022/01/04

REPOSITORIES: GEO

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EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

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