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Myeloid-derived suppressor cell and macrophage exert distinct angiogenic and immunosuppressive effects in breast cancer.

ABSTRACT: The immunosuppressive tumor microenvironment is a key obstacle to hinder a cancer immunotherapy. Myeloid-derived suppressor cells (MDSCs) have been considered as a major player in immunosuppression. In this study, we find that tumor-infiltrating MDSCs (tiMDSCs) are less immunosuppressive than tumor-associated macrophages (TAMs) in multiple murine orthotopic breast tumor models. Compared to TAMs, tiMDSCs produce higher levels of pro-inflammatory factors and lower levels of anti-inflammatory factors. Furthermore, tiMDSCs are preferentially located in hypoxic areas and are more pro-angiogenic than TAMs. Consistent with these functional disparities, a shift from tiMDSCs to TAMs is observed during the progression of breast cancer. Moreover, infiltration of tiMDSCs is also noted in distal colonization of breast cancer cells in the lung. Taken together, our findings indicate that tiMDSCs are more pro-angiogenic and promote tumor initiation, while TAMs are more immunosuppressive and facilitate tumor immune evasion. This study suggests that selectively targeting on TAMs could alleviate the immunosuppressive tumor microenvironment and potentiate cancer immunotherapy.

SUBMITTER: Fang Z

PROVIDER: S-EPMC5589571 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Myeloid-derived suppressor cell and macrophage exert distinct angiogenic and immunosuppressive effects in breast cancer.

Fang Zhaoxu Z Wen Chengwen C Chen Xiaolan X Yin Rongping R Zhang Chenglin C Wang Xiaohua X Huang Yuhui Y

Oncotarget 20170410 33

The immunosuppressive tumor microenvironment is a key obstacle to hinder a cancer immunotherapy. Myeloid-derived suppressor cells (MDSCs) have been considered as a major player in immunosuppression. In this study, we find that tumor-infiltrating MDSCs (tiMDSCs) are less immunosuppressive than tumor-associated macrophages (TAMs) in multiple murine orthotopic breast tumor models. Compared to TAMs, tiMDSCs produce higher levels of pro-inflammatory factors and lower levels of anti-inflammatory facto ...[more]

PMID: 28903332

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Project description:BACKGROUND: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. Therefore, we examined 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 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. RESULTS:Cells 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. CONCLUSIONS:These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.

Dataset Information

Myeloid-derived suppressor cell and macrophage exert distinct angiogenic and immunosuppressive effects in breast cancer.

Publications

Myeloid-derived suppressor cell and macrophage exert distinct angiogenic and immunosuppressive effects in breast cancer.

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