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

Author:

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

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.

Funder

Ligue Contre le Cancer

Association pour la Recherche sur le Cancer

Agence Nationale de la Recherche

Cancéropôle Ile de France

Fondation pour la Recherche Médicale

Institut National Du Cancer

Institut National de la Santé et de la Recherche Médicale

Seerave Foundation

Assistance Publique - Hôpitaux de Paris

Cancer Prevention and Research Institute of Texas

Publisher

Frontiers Media SA

Subject

Immunology,Immunology and Allergy

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