<i>In Vivo</i> Epigenetic CRISPR Screen Identifies <i>Asf1a</i> as an Immunotherapeutic Target in <i>Kras</i> -Mutant Lung Adenocarcinoma

Abstract

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with <i>KRAS</i>-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an <i>in vivo</i> CRISPR screen in a <i>Kras</i> ^G12D/<i>Trp53</i> ^-/- LUAD model. Our data showed that loss of the histone chaperone <i>Asf1a</i> in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic <i>Asf1a</i> 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. SIGNIFICANCE: Using an <i>in vivo</i> epigenetic CRISPR screen, we identified <i>Asf1a</i> as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. <i>Asf1a</i> deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.<i>See related commentary by Menzel and Black, p. 179</i>.<i>This article is highlighted in the In This Issue feature, p. 161</i>.