Jacob Garritson

First Advisor

Hayward, Reid

Document Type

Dissertation

Date Created

8-2020

Embargo Date

3-2021

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

Local Identifiers

Garritson_unco_0161D_10875.pdf

Rights Statement

Copyright is held by the author.

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