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Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.
- Source :
-
Nature medicine [Nat Med] 2020 Jun; Vol. 26 (6), pp. 919-931. Date of Electronic Publication: 2020 May 25. - Publication Year :
- 2020
-
Abstract
- The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T <subscript>FH</subscript> ) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T <subscript>FH</subscript> cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T <subscript>FH</subscript> cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 <superscript>+</superscript> T <subscript>FH</subscript> cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.
- Subjects :
- Adenocarcinoma immunology
Adenocarcinoma microbiology
Adenocarcinoma pathology
Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents therapeutic use
Apoptosis immunology
Bacteroides fragilis
Cell Line, Tumor
Colonic Neoplasms immunology
Colonic Neoplasms microbiology
Colonic Neoplasms pathology
Epithelial Cells drug effects
Epithelial Cells immunology
Epithelial Cells pathology
Female
Firmicutes
Gastrointestinal Microbiome physiology
Humans
Ileum immunology
Ileum microbiology
Ileum pathology
Immunogenic Cell Death drug effects
Immunogenic Cell Death immunology
Immunologic Surveillance drug effects
Immunologic Surveillance immunology
Interleukin-12 immunology
Intestinal Mucosa
Lymphocytes, Tumor-Infiltrating immunology
Male
Mice
Middle Aged
Oxaliplatin therapeutic use
Prognosis
Programmed Cell Death 1 Receptor antagonists & inhibitors
Receptors, Interleukin-1 Type I immunology
T-Lymphocytes, Helper-Inducer drug effects
T-Lymphocytes, Helper-Inducer immunology
Adenocarcinoma drug therapy
Antineoplastic Agents pharmacology
Apoptosis drug effects
Colonic Neoplasms drug therapy
Gastrointestinal Microbiome immunology
Ileum drug effects
Lymphocytes, Tumor-Infiltrating drug effects
Oxaliplatin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 26
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32451498
- Full Text :
- https://doi.org/10.1038/s41591-020-0882-8