Bacterial-Driven Inflammation and Mutant BRAF Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy
Open Access
- 24 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 11 (7), 1792-1807
- https://doi.org/10.1158/2159-8290.CD-20-0770
Abstract
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 BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (Min(Apc Delta 716/+)) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAF(V600E) mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAF(V600E)Lgr5(Cre)Min (BLM) mice, tumors have similarities to human BRAF(V600E) tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8(+) T cells, express IFN gamma 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. SIGNIFICANCE: Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene-microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAF(V600E)Lgr5CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFN gamma-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.Other Versions
Funding Information
- NCI (P30CA006973)
- NCI (P30CA006973)
- National Institute of Environmental Health Sciences National Institutes of Health (R01 ES023183)
- National Institute of Environmental Health Sciences National Institutes of Health (R01 ES011858)
- Bloomberg Philanthropies Cancer Research UK (#C10674/A27140)
- Swim Across America and National Cancer Institute National Institutes of Health (R01 CA203891)
This publication has 50 references indexed in Scilit:
- A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic InterventionCancer Cell, 2013
- Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune EscapeScience Translational Medicine, 2012
- Coordinated regulation of myeloid cells by tumoursNature Reviews Immunology, 2012
- Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG IslandsCancer Cell, 2011
- Mast cell-orchestrated immunity to pathogensNature Reviews Immunology, 2010
- A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responsesNature Medicine, 2009
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- Identification of stem cells in small intestine and colon by marker gene Lgr5Nature, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- RAF/RAS oncogenes and mismatch-repair statusNature, 2002