CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-1448
Entities
People
- Cun Liao
- Feifei Zhang
- Guangchuan Wang
- Kristin Kim
- Leilei Niu
- Lupeng Ye
- Lvyun Zhu
- Matthew B. Dong
- Paul A Clark
- Paul A. Renauer
- Ryan D Chow
- Sidi Chen
- Xiaoya Zhang
- Xiaoyun Dai
- Yaying Du
- Youssef Errami
- Yujing Cheng
- Zhi-Gang Bai
- Zhiyuan Chu
Organizations
- Breast Cancer Alliance
- Mary Kay Foundation
- Melanoma Research Alliance
- National Institutes of Health
- St. Baldrick's Foundation
- V Foundation for Cancer Research
- Yale University