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

Author:

Deng Nan1ORCID,Reyes-Uribe Laura1ORCID,Fahrmann Johannes F.1ORCID,Thoman Whittney S.1ORCID,Munsell Mark F.2ORCID,Dennison Jennifer B.1ORCID,Murage Eunice1ORCID,Wu Ranran1ORCID,Hawk Ernest T.1ORCID,Thirumurthi Selvi34ORCID,Lynch Patrick M.34ORCID,Dieli-Conwright Christina M.56ORCID,Lazar Alexander J.78ORCID,Jindal Sonali9ORCID,Chu Khoi9ORCID,Chelvanambi Manoj10ORCID,Basen-Engquist Karen11ORCID,Li Yisheng2ORCID,Wargo Jennifer A.810ORCID,McAllister Florencia141213ORCID,Allison James P.912ORCID,Sharma Padmanee91214ORCID,Sinha Krishna M.1ORCID,Hanash Samir1ORCID,Gilchrist Susan C.115ORCID,Vilar Eduardo1413ORCID

Affiliation:

1. 1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

2. 2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

3. 3Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson, Houston, Texas.

4. 4Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.

5. 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

6. 6Department of Medicine, Harvard Medical School, Boston, Massachusetts.

7. 7Department of Behavioral Science, The University of Texas MD Anderson, Houston, Texas.

8. 8Department of Genomic Medicine, The University of Texas MD Anderson, Houston, Texas.

9. 9The Immunotherapy Platform, The University of Texas MD Anderson, Houston, Texas.

10. 10Department of Surgical Oncology, The University of Texas MD Anderson, Houston, Texas.

11. 11Department of Behavioral Science, The University of Texas MD Anderson, Houston, Texas.

12. 12Department of Immunology, The University of Texas MD Anderson, Houston, Texas.

13. 13Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson, Houston, Texas.

14. 14Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, Texas.

15. 15Department of Cardiology, The University of Texas MD Anderson, Houston, Texas.

Abstract

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.

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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