{"doi":"10.1158/2159-8290.c.6547756.v1","title":"Data from CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade","abstract":"<div>Abstract<p>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. <i>KMT2D</i> encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. <i>Kmt2d</i> loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, <i>Kmt2d</i>-mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, <i>Kmt2d</i>-mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that <i>Kmt2d</i> 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.</p>Significance:<p>ICB is ineffective in the majority of patients. Through direct <i>in vivo</i> CRISPR mutagenesis screening in GEMMs of cancer, we find <i>Kmt2d</i> deficiency sensitizes tumors to ICB. Considering the prevalence of <i>KMT2D</i> mutations, this finding potentially has broad implications for patient stratification and clinical decision-making.</p><p><i>This article is highlighted in the In This Issue feature, p. 1775</i></p></div>","journal":null,"year":2023,"id":405937,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":254235,"name":"Ryan D. Chow","orcid":"0000-0002-1872-6307","position":1,"is_corresponding":false},{"id":259568,"name":"Lvyun Zhu","orcid":"0000-0003-2288-5981","position":2,"is_corresponding":false},{"id":259569,"name":"Zhigang Bai","orcid":"0000-0001-9234-9354","position":3,"is_corresponding":false},{"id":259570,"name":"Lupeng Ye","orcid":"0000-0003-3901-6598","position":4,"is_corresponding":false},{"id":1095271,"name":"Feifei Zhang","orcid":"0000-0002-6137-4888","position":5,"is_corresponding":false},{"id":259572,"name":"Paul Renauer","orcid":"0000-0002-8747-0552","position":6,"is_corresponding":false},{"id":246108,"name":"Matthew B. Dong","orcid":"0000-0003-2553-5186","position":7,"is_corresponding":false},{"id":259573,"name":"Xiaoyun Dai","orcid":"0000-0002-6162-5202","position":8,"is_corresponding":false},{"id":259574,"name":"Xiaoya Zhang","orcid":"0000-0002-1614-0011","position":9,"is_corresponding":false},{"id":259575,"name":"Yaying Du","orcid":"0000-0002-3213-5722","position":10,"is_corresponding":false},{"id":261336,"name":"Yujing Cheng","orcid":null,"position":11,"is_corresponding":false},{"id":1184746,"name":"Leilei Niu","orcid":"0009-0001-7838-7730","position":12,"is_corresponding":false},{"id":259577,"name":"Zhiyuan Chu","orcid":"0000-0002-3193-5031","position":13,"is_corresponding":false},{"id":259578,"name":"Kristin Kim","orcid":"0000-0003-1220-8338","position":14,"is_corresponding":false},{"id":259579,"name":"Cun Liao","orcid":"0000-0002-7780-9575","position":15,"is_corresponding":false},{"id":1184747,"name":"Paul C. Clark","orcid":"0000-0002-4834-043X","position":16,"is_corresponding":false},{"id":259581,"name":"Youssef Errami","orcid":"0000-0002-0432-4331","position":17,"is_corresponding":false},{"id":60778,"name":"Sidi Chen","orcid":"0000-0002-3819-5005","position":18,"is_corresponding":false},{"id":259567,"name":"Guangchuan Wang","orcid":"0000-0001-5315-1599","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:20:59.152593Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}