Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

Marine Fidelle, Satoru Yonekura, Marion Picard, Alexandria Cogdill, Antoine Hollebecque, Maria Paula Roberti, Laurence Zitvogel

    Research output: Contribution to journalReview articlepeer-review

    55 Citations (Scopus)

    Abstract

    While colorectal cancers (CRC) are paradigmatic tumors invaded by effector memory lymphocytes, the mechanisms accounting for the relative resistance of MSI negative CRC to immunogenic cell death mediated by oxaliplatin and immune checkpoint inhibitors has remained an open conundrum. Here, we propose the viewpoint where its microenvironmental contexture could be explained -at least in part- by macroenvironmental cues constituted by the complex interplay between the epithelial barrier, its microbial ecosystem, and the local immune system. Taken together this dynamic ménage-à-trois offers novel coordinated actors of the humoral and cellular immune responses actionable to restore sensitivity to immune checkpoint inhibition. Solving this paradox involves breaking tolerance to crypt stem cells by inducing the immunogenic apoptosis of ileal cells in the context of an ileal microbiome shifted towards immunogenic bacteria using cytotoxicants. This manoeuver results in the elicitation of a productive Tfh and B cell dialogue in mesenteric lymph nodes culminating in tumor-specific memory CD8+ T cell responses sparing the normal epithelium.

    Original languageEnglish
    Article number600886
    JournalFrontiers in Immunology
    Volume11
    DOIs
    Publication statusPublished - 14 Dec 2020

    Keywords

    • Bacteroides fragilis
    • Fusobacterium nucleatum
    • colon cancer
    • ileum
    • immune checkpoint
    • immunity
    • microbiome

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