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Hayward, Reid

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Breast cancer (BC) is one of the leading causes of cancer deaths among females. It is well known that the presence of a tumor decreases robust anticancer immunity via immune-modulation and enhanced immunosuppression through a process called cancer immunoediting. However, it has yet to be determined if exercise-based rehabilitation can elevate the peripheral anticancer immune profile and reduce myeloid-derived suppressor cell (MDSC) mediated immunosuppression. Purpose: To assess the effects of a 12-week prescribed, individualized, supervised exercise-based rehabilitation program on selected circulating immune cells in BC patients at the University of Northern Colorado Cancer Rehabilitation Institute. Methods: 16 female BC patients currently undergoing treatment were divided into a control group (CON, n=7), engaging in normal activities of daily living, and an exercise group (EX, n=9) that participated in 12-weeks of personalized combined aerobic and resistance training three times a week. Venous blood was collected before and after the intervention period and circulating immune cells will be analyzed for frequency and function using flow cytometry. Results: Early (E-) MDSC levels were significantly lower after the exercise intervention compared to the CON group (CON: 18.2±14.5% vs. EX: 5.3±3.6%, p<0.05). Monocytic (M-) MDSC showed a non-significant change of +48% in the CON group at POST (CON: PRE: 4.5±5.1% vs. POST: iv 6.8±4.5%), while POST M-MDSC levels displayed a non-significant change of -40% in the EX group (EX: PRE 4.9±2.6% vs. POST: 2.9±1.7%). An alternative MDSC phenotype analysis revealed that exercise significantly decreased M-MDSC from PRE to POST in the EX group (0.15±0.13% vs. 0.05± 0.03%, p<0.05), but not in the CON group (0.10±0.11% vs. 0.06±0.05%). There was no effect of exercise on MDSC suppressive activity or type I interferon receptor (IFNAR1) protein expression. The EX group displayed significantly higher levels of circulating Natural Killer (NK) cell frequencies than CON at the POST timepoint (3.5± 6.5 vs. 1.5±3.0 % of CD3- cells, p<0.05), where NK cell level changes were -75% for CON vs. +2% for EX from PRE to POST. There was a significant reduction in CD8+ cytotoxic T lymphocyte (CTLs) and CD4+ T helper (Th) cell frequencies in the EX group when comparing PRE to POST (CTLs: 23.6±10.8 vs. 16.1±10.1 % of CD3+ cells; Th: 41.3±24.3 vs. 27.5±21.1 % of CD3+ cells, p<0.05) Exercise showed no effect on Nur77+ activation status of the these lymphocytes, although percentage changes were +248% vs. -41% and +206% vs. -7% for CTLs and Th cell positive frequency for Nur77, respectively, for CON vs. EX from PRE to POST. Exercise caused a greater increase in Granzyme B (GZB)+ CTLs (+6%) when compared to the control group (+0.5%), and there was a greater yet non-significant percentage change of perforin expressing CTLs and NK cells in the CON group (-16 to -19%) compared to the exercising subjects (-0.5 to -5%). Discussion: Immune modulation remains a major target of interest to fight cancer using novel pharmaceutical and lifestyle interventions such as exercise. This dissertation study suggests that exercise may not be able to fully normalize but rather maintain certain peripheral immune cell frequencies and characteristics, offset the expansion of immunosuppressive cells, and potentially lower systemic inflammation levels. In conclusion, 12-weeks of exercise-based rehabilitation may positively alter some circulating immune cells and at least partially normalize the peripheral anticancer immune profile in BC patients undergoing treatment.


154 pages

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