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>