A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.
basic_science · Level V
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- Record sourced from PubMed, PMID 37289890.
- Also identified by DOI 10.1126/science.abo2296.
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Abstract
Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by <i>Enterocloster</i> species drove the emigration of enterotropic α4β7<sup>+</sup>CD4<sup>+</sup> regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of <i>Enterocloster</i> species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.
Medical subject headings
- Anti-Bacterial Agents
- Cell Adhesion Molecules
- Drug Resistance, Neoplasm
- Gastrointestinal Microbiome
- Immune Checkpoint Inhibitors
- Immune Tolerance
- Immunologic Surveillance
- Integrins
- Mucoproteins
- Neoplasms