Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs

Abstract

Background: Solid tumors produce proteins that can induce the accumulation of bone marrow-derived cells in various tissues, and these cells can enhance metastatic tumor growth by several mechanisms. 4T1 murine mammary tumors are known to produce granulocyte colony-stimulating factor (G-CSF) and increase the numbers of immunosuppressive CD11b + Gr1 + myeloid-derived suppressor cells (MDSCs) in tissues such as the spleen and lungs of tumor-bearing mice. While surgical resection of primary tumors decreases MDSC levels in the spleen, the longevity and impact of MDSCs and other immune cells in the lungs after tumor resection have been less studied. Methods: We used mass cytometry time of flight (CyTOF) and flow cytometry to quantify MDSCs in the spleen, peripheral blood, and lungs of mice bearing orthotopic murine mammary tumors. We also tested the effect of primary tumor resection and/or gemcitabine treatment on the levels of MDSCs, other immune suppressor and effector cells, and metastatic tumor cells in the lungs. Results: We have found that, similar to mice with 4T1 tumors, mice bearing metastatic 4T07 tumors also exhibit accumulation of CD11b + Gr1 + MDSCs in the spleen and lungs, while tissues of mice with non-metastatic 67NR tumors do not contain MDSCs. Mice with orthotopically implanted 4T1 tumors have increased granulocytic (G-) MDSCs, monocytic (M-) MDSCs, macrophages, eosinophils, and NK cells in the lungs. Resection of primary 4T1 tumors decreases G-MDSCs, M-MDSCs, and macrophages in the lungs within 48 h, but significant numbers of functional immunosuppressive G-MDSCs persist in the lungs for 2 weeks after tumor resection, indicative of an environment that can promote metastatic tumor growth. The chemotherapeutic agent gemcitabine depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils in the lungs of 4T1 tumor-bearing mice, and we found that treating mice with gemcitabine after primary tumor resection decreases residual G-MDSCs in the lungs and decreases subsequent metastatic growth.

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

“…Consequently, treatment with all-trans-retinoic acid (ATRA) induces the differentiation of MDSCs to DCs and macrophages reducing their immunosuppressive activity, while ameliorates the efficacy of anti-VEGFR2 immunotherapy [63,86]. Bennewith's group demonstrated the importance of monitoring the presence of MDSCs in a mice model of metastatic breast cancer, indicating the role of MDSCs in correlation with increased metastatic potential [87]. It constitutes a common notion that multiple signaling pathways are involved in cancer metastasis and angiogenesis.…”

miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer

“…Meanwhile, myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immune cells from the myeloid lineage, which serve as suppressors of antitumor immunity, have been found to contribute to the immunosuppressive microenvironment during tumor development [5]. Therapeutic strategies targeting MDSCs in combination with primary mammary tumor resection has also been reported to reduce and retard metastatic growth in the lungs in mice bearing orthotopic murine mammary tumors [6]. Additionally, studies have shown that targeting MDSC recruitment and enhancing antitumor immunity can augment the therapeutic efficacy of ablative hypofractionated radiation therapy in subcutaneous tumors using syngeneic lung cancer [7].…”

An overview of the tumor microenvironment, from cells to complex networks (Review)

“…Immature myeloid cell recruitment. Tumor-secreted factors (IL1, IL6, GM-CSF, TGFβ, CXCL12) act at the level of the bone marrow and trigger an accelerated myelopoiesis, having as result immature myeloid cells (MDSCs), which accumulate in the tumor, leading to immunosuppression and favoring tumor growth (73). This phenomenon is more advanced as the tumor progresses.…”