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Research Articles

CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade

Guangchuan Wang, Ryan D. Chow, Lvyun Zhu, Zhigang Bai, Lupeng Ye, Feifei Zhang, Paul A. Renauer, Matthew B. Dong, Xiaoyun Dai, Xiaoya Zhang, Yaying Du, Yujing Cheng, Leilei Niu, Zhiyuan Chu, Kristin Kim, Cun Liao, Paul Clark, Youssef Errami and Sidi Chen
Guangchuan Wang
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Ryan D. Chow
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
4M.D.-Ph.D. Program, Yale University, West Haven, Connecticut.
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  • ORCID record for Ryan D. Chow
Lvyun Zhu
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Zhigang Bai
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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  • ORCID record for Zhigang Bai
Lupeng Ye
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Feifei Zhang
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Paul A. Renauer
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
5Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, Connecticut.
6Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, Connecticut.
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Matthew B. Dong
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
4M.D.-Ph.D. Program, Yale University, West Haven, Connecticut.
5Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, Connecticut.
7Immunobiology Program, Yale University, New Haven, Connecticut.
8Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
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Xiaoyun Dai
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Xiaoya Zhang
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Yaying Du
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Yujing Cheng
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Leilei Niu
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Zhiyuan Chu
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Kristin Kim
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Cun Liao
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Paul Clark
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Youssef Errami
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
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Sidi Chen
1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
2System Biology Institute, Yale University, West Haven, Connecticut.
3Center for Cancer Systems Biology, Yale University, West Haven, Connecticut.
4M.D.-Ph.D. Program, Yale University, West Haven, Connecticut.
5Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, Connecticut.
6Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, Connecticut.
7Immunobiology Program, Yale University, New Haven, Connecticut.
9Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
10Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut.
11Yale Stem Cell Center, Yale University School of Medicine, New Haven, Connecticut.
12Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut.
13Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, Connecticut.
14Yale Center for Biomedical Data Science, Yale University School of Medicine, New Haven, Connecticut.
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  • For correspondence: sidi.chen@yale.edu
DOI: 10.1158/2159-8290.CD-19-1448 Published December 2020
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Abstract

Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy in several cancer types. However, only a fraction of patients will respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMM) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. KMT2D encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, Kmt2d-mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that Kmt2d deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, and also highlight the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment.

Significance: ICB is ineffective in the majority of patients. Through direct in vivo CRISPR mutagenesis screening in GEMMs of cancer, we find Kmt2d deficiency sensitizes tumors to ICB. Considering the prevalence of KMT2D mutations, this finding potentially has broad implications for patient stratification and clinical decision-making.

This article is highlighted in the In This Issue feature, p. 1775

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2020;10:1912–33

  • Received December 10, 2019.
  • Revision received June 1, 2020.
  • Accepted September 1, 2020.
  • Published first September 4, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (12)
December 2020
Volume 10, Issue 12
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CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade
Guangchuan Wang, Ryan D. Chow, Lvyun Zhu, Zhigang Bai, Lupeng Ye, Feifei Zhang, Paul A. Renauer, Matthew B. Dong, Xiaoyun Dai, Xiaoya Zhang, Yaying Du, Yujing Cheng, Leilei Niu, Zhiyuan Chu, Kristin Kim, Cun Liao, Paul Clark, Youssef Errami and Sidi Chen
Cancer Discov December 1 2020 (10) (12) 1912-1933; DOI: 10.1158/2159-8290.CD-19-1448

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CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade
Guangchuan Wang, Ryan D. Chow, Lvyun Zhu, Zhigang Bai, Lupeng Ye, Feifei Zhang, Paul A. Renauer, Matthew B. Dong, Xiaoyun Dai, Xiaoya Zhang, Yaying Du, Yujing Cheng, Leilei Niu, Zhiyuan Chu, Kristin Kim, Cun Liao, Paul Clark, Youssef Errami and Sidi Chen
Cancer Discov December 1 2020 (10) (12) 1912-1933; DOI: 10.1158/2159-8290.CD-19-1448
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