Exercise boosts immune defense in Lynch syndrome patients

In a recent study published in Clinical Cancer Research, researchers explore the role of exercise in modulating inflammation and the resident immune system in the colonic mucosa of Lynch syndrome (LS) patients.

Study: Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-associated Immunity in Lynch Syndrome. Image Credit: Ground Picture / Shutterstock.com

About the study

LS, an inherited condition, increases the risk of endometrial and colorectal tumors. Exercise has been shown to reduce CRC risk in the general population; however, the biological effects of exercise on LS patients' immune systems remain unclear.

Previous studies have shown the modulatory effects of exercise on the gut microbiome, insulin growth factor signaling, and other pathways in CRC development, thereby promoting antitumorigenic activity. In the present study, researchers investigated the influence of cycling intervention on immune system biology among LS carriers.

The researchers recruited 21 CYCLE-P trial participants in an active cancer monitoring program at the University of Texas MD Anderson Cancer Center (MDACC) in either a one-year aerobic exercise intervention or standard care. The intervention consisted of three 45-minute weekly cycling lessons or regular care with one exercise therapy session as a control. There were 11 individuals in the intervention group and 10 individuals in the control group.

Between April 2018 and January 2019, the participants were recruited in the CYCLE-P trial. Adults between 18 and 50 years of age with LS were defined as carriers or obligate carriers by the pedigree of a pathogenic mutation in one of the four deoxyribonucleic acid (DNA) mismatch repair (MMR) genes, including the MutL protein homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, or PMS1 homolog 2 (PMS2).

Participants with a personal history of non-sporadic MMR-deficient neoplasia defined by immunohistochemistry or microsatellite instability (MSI) assessments or both were not included in the study. Likewise, individuals with a history of cardiovascular disease or uncontrolled medical disorders were excluded from the study.

In the prior six months, participants experienced no signs of ongoing or recurrent malignant illness or cancer-directed therapy. Only patients who agreed to an annual screening colonoscopy were considered. Participants were required to retain a part of their distal colon or rectosigmoid intact for normal mucosa samples to be collected.

Metabolomics, bulk messenger ribonucleic acid sequencing (mRNAseq), immunohistochemistry (IHC), spatial transcriptomics, and digital spatial profiling (DSP) were used to investigate the effects of exercise on cardiorespiratory fitness, circulating prostaglandin (PG) levels, and colorectal-tissue biomarkers.

At the initial visit, both the intervention and control groups had standard-of-care lower gastrointestinal (GI) flexible sigmoidoscopy or colonoscopy with biopsies and blood collection. Cardiopulmonary exercise testing (CPET) was performed within 30 days of the endoscopy at the second appointment. The intervention and standard care groups had a third visit at the one-year endoscopy, followed by CPET at the fourth appointment within 30 days of the one-year endoscopy.

Peak oxygen consumption (VO_2peak) was assessed by symptom-limited CPET on a bicycle with an electrocardiogram (ECG). Adherence was evaluated by self-reported email questionnaires.

A baseline health questionnaire was used to assess the regular use of aspirin, which was defined as three or more times each week. No patients who consumed aspirin were included in the study. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.

Study findings

The primary outcome was a statistically significant increase in oxygen intake (VO^2peak). In the exercise group, mean relative VO_2peak increased by 26% as compared to baseline, whereas the regular care group decreased by 1.4%. Cycling exercise also reduced inflammatory prostaglandin E2 (PGE2) levels in the blood and colon, as well as circulating triacyl-glycerides among LS carriers allocated to the intervention group.

The most common differentially expressed genes in the intervention group were the ATP Binding Cassette Subfamily G Member 8 (ABCG8), long intergenic non-protein coding RNA 2899 (LINC02899), Potassium Voltage-Gated Channel Modifier Subfamily V Member 1 (KCNV1), and Beta-1,4-N-Acetyl-Galactosaminyltransferase 2 (B4GALNT2). The down-regulated genes were the PRAC1/2 small nuclear protein (PRAC1/2), Homeobox B13 (HOXB13), and Transmembrane Serine Protease 6 (TMPRSS6).

The most activated pathways in the exercise group were associated with the immunological system, including Th1, Th2, and Th17 cellular differentiation, as well as Toll-like signaling. Growth, survival, proliferation, and differentiation signals such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and Ras-related protein 1 (Rap1), as well as key cellular processes such as DNA replication and cell cycle control, were also highly activated in the exercise group.

Pathways associated with heart muscle contraction, oxidative phosphorylation, synaptic vesicle cycle, and ribosomal function were the most inhibited pathways in the intervention group.

These findings indicate that exercise plays an important role in developing innate and adaptive immune responses in a high-risk cancer group. The AE rate by grade did not differ between the exercise and usual care groups.

Conclusions

Aerobic exercise decreased inflammation and promoted intestinal mucosa-associated protective immunity among individuals with LS, thus demonstrating that exercise training could help prevent cancer in this patient population. However, randomized controlled trials are required to further explore the preventive effectiveness of aerobic exercises in LS patients.

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.