@article{775fcd61c6854d0a98b5949a79395db1,
title = "Bacterial-driven inflammation and mutant braf expression combine to promote murine colon tumorigenesis that is sensitive to immune checkpoint therapy",
abstract = "Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, muta-gens, 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 (MinApc∆716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAFV600E mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAFV600ELgr5CreMin (BLM) mice, tumors have similarities to human BRAFV600E 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 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. 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 BRAFV600ELgr5CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.",
author = "{Destefano Shields}, {Christina E.} and White, {James R.} and Liam Chung and Alyssa Wenzel and Hicks, {Jessica L.} and Tam, {Ada J.} and Chan, {June L.} and Dejea, {Christine M.} and Hongni Fan and John Michel and Maiuri, {Ashley R.} and Shruthi Sriramkumar and Ram Podicheti and Rusch, {Douglas B.} and Hao Wang and {De Marzo}, {Angelo M.} and Sepideh Besharati and Anders, {Robert A.} and Baylin, {Stephen B.} and O{\textquoteright}hagan, {Heather M.} and Franck Housseau and Sears, {Cynthia L.}",
note = "Funding Information: Support for this research was provided from the following grants: National Institute of Environmental Health Sciences, National Institutes of Health grants R01 ES023183 (to H.M. O{\textquoteright}Hagan) and R01 ES011858 (to S.B. Baylin); Bloomberg Philanthropies, Cancer Research UK grant C10674/A27140 and institutional resources from JHU SOM and DOM (to C.L. Sears); Swim Across America and National Cancer Institute, National Institutes of Health grant R01 CA203891 (to F. Housseau). Funding Information: J.R. White reports personal fees from Resphera Biosciences, LLC outside the submitted work. J. Michel reports grants from the NIH outside the submitted work. R.A. Anders reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck SD and Incyte, and grants and personal fees from RAPT Biotech outside the submitted work. H.M. O{\textquoteright}Hagan reports grants from the NIH and the Indiana Clinical and Translational Sciences Institute during the conduct of the study. F. Housseau reports grants from the NIH/NCI and Swim Across America during the conduct of the study. C.L. Sears reports grants from Bloomberg Philanthropies and Cancer Research UK Grand Challenge during the conduct of the study, as well as grants from Janssen and Bristol Myers Squibb outside the submitted work. No disclosures were reported by the other authors. Funding Information: We thank Dr. David L. Huso for contributions in evaluating the pathology of this model, the Indiana University Center for Genomics and Bioinformatics and the Indiana Molecular Biology Institute for their assistance, members of the Sidney Kimmel Comprehensive Cancer Center Experimental and Computational Genomics Core (supported by NCI grant P30CA006973) for their support with RNA-seq, and the Johns Hopkins University Oncology Tissue Services for tissue processing and slides (supported by NCI grant P30CA006973). Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = jul,
doi = "10.1158/2159-8290.CD-20-0770",
language = "English (US)",
volume = "11",
pages = "1792--1807",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "7",
}