Using CRISPR-edited genetically engineered mouse models (CRISPR-GEMMs) to screen nearly 50 commonly mutated tumor suppressor genes, Wang, Chow, Zhu, and Bai et al. found that mutations in Kmt2d (a methyltransferase) enhanced immune infiltration and responses to checkpoint blockade (ICB) across multiple cancer types. Loss of Kmt2d led to increased DNA damage, mutation burden, and intron retention; altered chromatin accessibility; activation of transposable elements; increased protein degradation; and increased IFNγ-stimulated antigen presentation, thus enhancing tumor immunogenicity. KMT2D could serve as a biomarker for ICB efficacy.
Contributed by Lauren Hitchings
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-GEMMs) 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 cancer patients. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. Additionally, Kmt2d-mutant cells exhibit increased protein turnover and IFN-_-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human are 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.
Author Info: (1) Genetics, Systems Biology Institute, Yale University. (2) Genetics, Systems Biology Institute, Yale University. (3) Genetics, Systems Biology Institute, Yale University. (4) Ge
Author Info: (1) Genetics, Systems Biology Institute, Yale University. (2) Genetics, Systems Biology Institute, Yale University. (3) Genetics, Systems Biology Institute, Yale University. (4) Genetics, Systems Biology Institute, Yale University. (5) Genetics, Systems Biology Institute, Yale University. (6) Genetics, Systems Biology Institute, Yale University. (7) Genetics, Systems Biology Institute, Yale University. (8) Genetics, Systems Biology Institute, Yale University. (9) Genetics, Systems Biology Institute, Yale University. (10) Genetics, Systems Biology Institute, Yale University. (11) Genetics, Systems Biology Institute, Yale University. (12) Genetics, Systems Biology Institute, Yale University. (13) Genetics, Systems Biology Institute, Yale University. (14) Genetics, Systems Biology Institute, Yale University. (15) Genetics, Systems Biology Institute, Yale University. (16) Genetics, Systems Biology Institute, Yale University. (17) Genetics, Systems Biology Institute, Yale University. (18) Genetics, Systems Biology Institute, Yale University. (19) Genetics, Systems Biology Institute, Yale University sidi.chen@yale.edu.
