Bacterial-Driven Inflammation and Mutant BRAF Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy.

Autor:	DeStefano Shields CE; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland., White JR; Resphera Biosciences, Baltimore, Maryland., Chung L; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland., Wenzel A; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Hicks JL; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Tam AJ; Bloomberg-Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Flow Cytometry Technology Development Center, Bloomberg-Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland., Chan JL; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Dejea CM; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Fan H; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Michel J; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland., Maiuri AR; Medical Sciences, Cell, Molecular and Cancer Biology Program, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Bloomington, Indiana., Sriramkumar S; Medical Sciences, Cell, Molecular and Cancer Biology Program, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Bloomington, Indiana., Podicheti R; Center for Genomics and Bioinformatics, Indiana University, Bloomington, Indiana., Rusch DB; Center for Genomics and Bioinformatics, Indiana University, Bloomington, Indiana., Wang H; Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland., De Marzo AM; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Besharati S; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Anders RA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Baylin SB; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland., O'Hagan HM; Medical Sciences, Cell, Molecular and Cancer Biology Program, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Bloomington, Indiana. hmohagan@indiana.edu fhousse1@jhmi.edu csears@jhmi.edu., Housseau F; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. hmohagan@indiana.edu fhousse1@jhmi.edu csears@jhmi.edu.; Bloomberg-Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Flow Cytometry Technology Development Center, Bloomberg-Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland., Sears CL; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. hmohagan@indiana.edu fhousse1@jhmi.edu csears@jhmi.edu.; Bloomberg-Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2021 Jul; Vol. 11 (7), pp. 1792-1807. Date of Electronic Publication: 2021 Feb 25.
DOI:	10.1158/2159-8290.CD-20-0770
Abstrakt:	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 ApcΔ716/+ ) 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 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 BRAF V600E Lgr5 Cre Min mice, wherein tumors phenocopy aspects of human BRAF -mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade. This article is highlighted in the In This Issue feature, p. 1601 . (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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