Date Created

8-2020

Embargo Date

3-2021

Document Type

Dissertation

Department

College of Natural and Health Sciences, Kinesiology Nutrition and Dietetics, KiND Student Work

First Advisor

Hayward, Reid

Abstract

Garritson, Jacob. Effects of Exercise on Myeloid-Derived Suppressor Cell-Related Tumor Progression and Metastasis. Published Doctoral Dissertation, University of Northern Colorado, 2020. Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Purpose: to determine the effects of physical activity on MDSC accumulation and function. Methods: Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor cell injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs (CD11b/Ly6G/Ly6C). MDSCs were purified from the spleen to assess T-cell suppressive capacity and metastatic lesions were quantified in the lung. Results Compared to SED+TUM, levels of MDSCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33 ± 5%; 23 ± 10% of total cells, respectively) and day 20 (34 ± 8%; 24 ± 5% of total cells, respectively). Additionally, there were significantly fewer circulating MDSCs (p < 0.05) in WR+TUM at day 16 and there was a non-significant (p = 0.08) trend toward lower MDSCs at day 28 in the tumors of WR+TUM. While this delay in MDSC accumulation did not translate to a decrease in tumor growth, physical activity led to 62% and 26% fewer metastatic lung nodules at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T-cell proliferation (3.2 ± 1.3 proliferation index) while T-cell proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls. Conclusions: These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for early interventions with increasingly common immunotherapies.

Extent

87 pages

Rights Statement

Copyright is held by the author.

Comments

Fall 2020 Graduate Dean's Citation for Outstanding Thesis, Dissertation, and Scholarly Project

Digital Origin

Born digital

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