American Association for Cancer Research
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21598290cd190780-sup-225096_2_supp_5888175_q0mty9.xlsx (199.95 kB)

Table S2 from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma

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posted on 2023-04-03, 22:21 authored by Fei Li, Qingyuan Huang, Troy A. Luster, Hai Hu, Hua Zhang, Wai-Lung Ng, Alireza Khodadadi-Jamayran, Wei Wang, Ting Chen, Jiehui Deng, Michela Ranieri, Zhaoyuan Fang, Val Pyon, Catríona M. Dowling, Ece Bagdatlioglu, Christina Almonte, Kristen Labbe, Heather Silver, Alexandra R. Rabin, Kandarp Jani, Aristotelis Tsirigos, Thales Papagiannakopoulos, Peter S. Hammerman, Vamsidhar Velcheti, Gordon J. Freeman, Jun Qi, George Miller, Kwok-Kin Wong

MAGeCK analysis of CRISPR screen

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NIH

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ARTICLE ABSTRACT

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS-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 in vivo CRISPR screen in a KrasG12D/Trp53−/− LUAD 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. Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti–PD-1 therapy. Asf1a 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.See related commentary by Menzel and Black, p. 179.This article is highlighted in the In This Issue feature, p. 161

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