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

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

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2023;29(21):4361-4372

PMID: 37724990

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Plain Language Summary

Lynch syndrome (LS) is a genetic disorder conferring a 60% lifetime risk of developing colorectal cancer (CRC). Exercise is associated with a reduction in CRC risk in the general population, potentially mediated via modulation of inflammation. The aim of this non-randomised, controlled trial was to test whether an intervention consisting of 3 x 45-minute cycling classes per week for 12 months affects inflammatory factors (prostaglandin E2, PGE2) in the colorectal mucosa and blood and whether this intervention is feasible in LS carriers. The control group received usual care with one session of exercise counselling. Of 60 patients invited to join the study, 21 (35%) agreed to take part. Of the 11 participants in the intervention group, 9 (81.2%) completed the study with an average adherence to the intervention of 51.3%, compared to 7/10 completing in the control group. VO2 peak (maximal aerobic capacity) increased significantly in the intervention group, compared to the control group over the 12 months. Patients in the intervention group also had a significant reduction in colonic and systemic PGE2 levels compared to controls following intervention. Changes in gene expression which may reflect an increased immune surveillance of the colon were also observed in the intervention group. The authors concluded that the study confirmed that exercise may modulate inflammation in the colonic mucosa in patients at high risk of CRC and that further randomised studies are necessary to confirm the potential benefits of exercise for patients with LS.

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.

Address: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson, Houston, Texas.; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Department of Behavioral Science, The University of Texas MD Anderson, Houston, Texas.; Department of Genomic Medicine, The University of Texas MD Anderson, Houston, Texas.; The Immunotherapy Platform, The University of Texas MD Anderson, Houston, Texas.; Department of Surgical Oncology, The University of Texas MD Anderson, Houston, Texas.; Department of Immunology, The University of Texas MD Anderson, Houston, Texas.; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson, Houston, Texas.; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, Texas.; Department of Cardiology, The University of Texas MD Anderson, Houston, Texas.

DOI: 10.1158/1078-0432.CCR-23-0088

Patient Centred Factor

Mediators: Inflammation

Clinical Imbalances

Immune and inflammation

Laboratory Testing

Blood Tissue biopsy

Modifiable Lifestyle Factors

Exercise and movement

Nutrition Evidence Keywords

Inflammation Exercise Colorectal cancer Gene expression Lynch Syndrome

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