Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

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

doi:10.1016/j.ccell.2023.12.006

Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

Cancer Cell. 2024 Jan 8;42(1):85-100.e6. doi: 10.1016/j.ccell.2023.12.006. Epub 2023 Dec 28.

Authors

Affiliations

¹ Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Pediatrics and Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
³ Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Respiratory Diseases, Faculty of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
⁴ Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Resphera Biosciences, Baltimore, MD, USA.
⁸ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, USA.
⁹ Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: fmcallister@mdanderson.org.

PMID: 38157865
DOI: 10.1016/j.ccell.2023.12.006

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: B cells; IL-17; intestinal homeostasis; microbiome; pancreatic cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Humans
Interleukin-17*
Mice
Mice, Knockout
Pancreatic Neoplasms* / pathology
Receptors, Interleukin-17 / genetics
Signal Transduction

Substances

Interleukin-17
Receptors, Interleukin-17

Grants and funding

R37 CA237384/CA/NCI NIH HHS/United States