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Cancer Discov. 2020 Feb;10(2):270-287. doi: 10.1158/2159-8290.CD-19-0780. Epub 2019 Nov 19.

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

Author information

1
Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
2
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
5
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR.
6
Applied Bioinformatics Laboratories and Genome Technology Center, Division of Advanced Research Technologies, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
7
S. Arthur Localio Laboratory, Department of Surgery, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
8
State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
9
Department of Pathology, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
11
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
12
Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York. kwok-kin.wong@nyumc.org.

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 Kras G12D/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. SIGNIFICANCE: 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.

PMID:
31744829
PMCID:
PMC7007372
[Available on 2020-08-01]
DOI:
10.1158/2159-8290.CD-19-0780
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