Abstract
BackgroundMyeloid-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. Therefore, we examined the effects of physical activity on MDSC accumulation and function.MethodsFemale 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 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.ResultsCells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed 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 proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls.ConclusionsThese findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.
Highlights
Myeloid-Derived Suppressor cells (MDSCs) are a heterogeneous population of immature immune cells that expand in response to cancer and various other pathological conditions
Cells expressing Myeloid-derived suppressor cells (MDSCs) biomarkers were detected in the spleen, blood, and tumor beginning at d16
Physical activity and myeloid derived suppressor cells suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in wheel run tumor (WR+TUM) MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls. These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies
Summary
Myeloid-Derived Suppressor cells (MDSCs) are a heterogeneous population of immature immune cells that expand in response to cancer and various other pathological conditions. Malignant cancer cells can disrupt normal myelopoiesis and increase production of MDSCs from the bone marrow by secreting systemic growth factors, pro-inflammatory cytokines, and signaling lipids [3]. Interleukin-6 (IL-6) and interleukin-1β (IL-1β) are pro-inflammatory cytokines that have been implicated as drivers of the accumulation of MDSCs in tumors and secondary lymphoid organs [10,11]. Modeling this tumor-dependent MDSC expansion has frequently relied on spontaneous or syngeneic transplantable tumors in immune-intact mice, both of which can lead to the pronounced expansion of both PMN- and M-MDSC cell populations detectable in the bone marrow, spleen and general circulation [12]. We examined the effects of physical activity on MDSC accumulation and function
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