{"doi":"10.1158/2159-8290.c.6549334","title":"Data from Bacterial-Driven Inflammation and Mutant <i>BRAF</i> Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy","abstract":"<div>Abstract<p>Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in <i>BRAF</i> are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (Min<sup>ApcΔ716/+</sup>) enterotoxigenic <i>Bacteroides fragilis</i> (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the <i>BRAF</i><sup>V600E</sup> mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized <i>BRAF</i><sup>V600E</sup><i>Lgr5</i><sup>Cre</sup>Min (BLM) mice, tumors have similarities to human <i>BRAF</i><sup>V600E</sup> tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8<sup>+</sup> T cells, express IFNγ signatures, and are sensitive to anti–PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy.</p>Significance:<p>Colorectal cancers with <i>BRAF</i> mutations have distinct characteristics. We present evidence of specific colorectal cancer gene–microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in <i>BRAF</i><sup>V600E</sup><i>Lgr5</i><sup>Cre</sup>Min mice, wherein tumors phenocopy aspects of human <i>BRAF</i>-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.</p><p><i>This article is highlighted in the In This Issue feature, p. 1601</i></p></div>","journal":null,"year":2023,"id":406066,"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":0.9516,"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":29183,"name":"James R. 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