Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome

Authors

Nan Deng
Laura Reyes-Uribe
Johannes F Fahrmann
Whittney S Thoman
Mark F Munsell
Jennifer B Dennison
Eunice Murage
Ranran Wu
Ernest T Hawk
Selvi Thirumurthi
Patrick M Lynch
Christina M Dieli-Conwright
Alexander J Lazar
Sonali Jindal
Khoi Chu
Manoj Chelvanambi
Karen Basen-Engquist
Yisheng Li
Jennifer A Wargo
Florencia McAllister
James P Allison
Padmanee Sharma
Krishna M Sinha
Samir Hanash
Susan C Gilchrist
Eduardo Vilar

Publication Date

11-1-2023

Journal

Clinical Cancer Research

Abstract

PURPOSE: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers.

PATIENTS AND METHODS: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx.

RESULTS: We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies.

CONCLUSIONS: Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.

Keywords

Female, Humans, Colorectal Neoplasms, Hereditary Nonpolyposis, Exercise, Endometrial Neoplasms, Gene Expression Profiling, Intestinal Mucosa

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Supplementary Materials

PMID: 37724990