Exercise Reduces Proportions of Tumor Resident Myeloid‐Derived Suppressor Cells

Abstract

Myeloid‐derived suppressor cells (MDSCs) are a population of immature myeloid immune cells that promote tumor progression and metastasis by suppressing both innate and adaptive immune responses. Exercise modulates immune function and is generally thought to protect against tumor growth and metastasis, yet the mechanisms behind this protection are largely unknown.PURPOSETo examine how exercise impacts circulating and tissue resident lymphocyte and MDSC populations.METHODSFemale mice were randomly assigned to treatment groups: exercise tumor (EX+TUM), sedentary tumor (SED+TUM), exercise (EX) or sedentary control (SED). EX groups underwent wheel running preconditioning for 6 weeks before tumor challenge. Following the 6‐week training period, animals in TUM groups were inoculated in the mammary fat pad with 1×104 4T1 mammary carcinoma cells and ran an additional 4‐weeks. Proportions of CD4+, CD8+, and CD335+ lymphocytes, as well as total MDSCs (CD11b+Ly6C+ Monocytic MDSCs (M‐MDSC) plus CD11b+Ly6G+ polymorphonuclear MDSCs (PMN‐MDSC)) were analyzed by flow cytometry in spleen, blood, and tumor.RESULTSNo effect of exercise was observed in CD4+ or CD8+ lymphocyte populations. The 4T1 mammary tumors significantly expanded MDSC populations in both spleen and blood regardless of exercise treatment. This tumor‐induced MDSC expansion was associated with enlarged spleens in sedentary animals (SED+TUM: 0.62g ± 0.11g) whereas the spleens in exercised animals with tumors were smaller (EX+TUM: 0.44g ± 0.11g) and did not differ from controls (EX: 0.08g ± 0.01g and SED: 0.11g ± 0.01g). Although there was no change in tumor volumes or tumor weights, exercise significantly reduced proportions of tumor‐infiltrating MDSCs (EX+TUM: 4.1% ± 1.6% vs. SED+TUM: 15.9% ± 2.3%). Further, tumor‐bearing exercised animals maintained a higher proportion of CD335+ natural killer cells in their spleens (EX+TUM: 0.6% ± 0.3%) relative to sedentary animals (SED+TUM: 0.4% ± 0.1%), which showed significant splenic CD335+ depletion relative to EX (1.3% ± 0.6%) controls.CONCLUSIONSThe observed reduction in tumor‐resident MDSCs suggests that exercise may improve antitumor immunity by decreasing MDSC‐related immune suppression in the tumor microenvironment and by preserving CD335+ lymphocyte populations. Exercise may reduce the severity of the aberrant myelopoiesis in tumor bearing animals as is evident by reduced splenomegaly in exercised animals.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Exercise on Breast Cancer: A Systematic Review and Meta-analysis of Animal Experiments

“…Among the included studies, 21 studies ( Steiner et al, 2013 ; Shalamzari et al, 2014 ; Alvarado et al, 2017 ; Alizadeh et al, 2018 ; Murphy et al, 2011 ; Aveseh et al, 2015 ; Leila et al, 2015 ; Malicka et al, 2015 ; Isanejad et al, 2016 ; Cui, 2017 ; Nasiri et al, 2017 ; Lyv Di et al, 2021 ; Qi et al, 2013 ; Siewierska et al, 2018 ; Siewierska et al, 2020 ; Wen et al, 2010 ; Gholamian et al, 2020 ; Vulczak et al, 2020 ; Wennerberg et al, 2020 ) reported that exercise could decrease the tumor volume, 1 ( Faustino-Rocha et al, 2016 ) reported negative effects of exercise, and 2 ( Smeda et al, 2017 ; Garritson et al, 2019 ) reported that exercise had no effect on the tumor volume.…”

“…Experimental studies using animal models to mimic human disease can detail the onset, promotion, or progression of disease and identify the potential biological pathways ( Hoffman-Goetz, 2003 ; Ashcraft et al, 2016 ), yet the current results of animal studies in exercise on tumor or the intensity of exercise effect were heterogeneous. Some studies found exercises were effective to slow tumor growth ( Shalamzari et al, 2014 ; Alizadeh et al, 2018 ) and decrease tumor cell number of breast cancer ( Alvarado et al, 2017 ), while other studies reported exercises did not inhibit tumor initiation ( Steiner et al, 2013 ) or have no effect on the tumor volume ( Garritson et al, 2019 ). The reason may be related with the different cancer phenotypes, the different model established methods of mammary adenoma and different exercise schemes (type, duration, intensity, and frequency of exercise).…”