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In vivo epigenetic CRISPR screen identifies Asf1a as an immunotherapeutic target in Kras-mutant lung adenocarcinoma

ABSTRACT: Despite substantial progress in lung cancer immunotherapy, the overall response rate in KRAS-mutant lung adenocarcinoma (ADC) patients remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responsesâ€”such as epigenetic modulation of anti-tumor immunityâ€”is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused sgRNA library, and performed an in vivo CRISPR screen in KrasG12D/P53-/- (KP) lung ADC model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of Asf1a inhibition and anti-PD-1 immunotherapy.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE138571 | GEO | 2019/11/26

REPOSITORIES: GEO

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Single-cell transcriptomic profiling of mouse KrasG12DP53-/- (KP) lung tumors in response to tumor cell intrinsic Asf1a knockout (KO), anti-PD-1 or combination treatment (Asf1a KO + anti-PD-1).

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