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

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. encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, -mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, -mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that 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 CRISPR mutagenesis screening in GEMMs of cancer, we find deficiency sensitizes tumors to ICB. Considering the prevalence of mutations, this finding potentially has broad implications for patient stratification and clinical decision-making..