Gut Epithelial Interleukin-17 Receptor a Signaling Can Modulate Distant Tumors Growth Through Microbial Regulation

Authors

Vidhi Chandra
Le Li
Olivereen Le Roux
Yu Zhang
Rian M Howell
Dhwani N Rupani
Seyda Baydogan
Haiyan D Miller
Erick Riquelme
Joseph Petrosino
Michael P Kim
Krishna P L Bhat
James R White
Jay K Kolls
Yuliya Pylayeva-Gupta
Florencia McAllister

Publication Date

1-8-2024

Journal

Cancer Cell

Abstract

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.

Keywords

Mice, Animals, Humans, Interleukin-17, Receptors, Interleukin-17, Mice, Knockout, Signal Transduction, Pancreatic Neoplasms

Comments

Supplementary Material

PMID: 38157865

DOI

10.1016/j.ccell.2023.12.006

PMID

38157865

PMCID

PMC11238637

PubMedCentral® Posted Date

July 2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes