Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling

Abstract

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T cell activation. Mechanistic investigations indicated that these effects relied upon crosstalk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL-6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide (NO), leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH crosstalk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape.

Mechanism of immune evasion in breast cancer

“…MDSC accumulation can inhibit mature DCs and the antitumor immune response. Additionally, the enhanced stem-like qualities of BC cells and lower activation of T cells modulated by MDSCs were revealed recently 130. Mononuclear MDSCs can differentiate into macrophages and mature DCs via modulation of nitric oxide, inhibitory cytokines, and arginase-1.…”

Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs

“…Patient-derived xenograft (PDX) tumor models were established as described (Peng et al, 2016). In brief, serially passaged PDX tumors were harvested at 700 to 1000 mm 3 from severe combined immunodeficient mice (CB-17 SCID), minced into ~4mm pieces and washed in high-glucose DMEM (Invitrogen) containing 1% L-glutamine (Invitrogen), 10% Fetal Bovine Serum (FBS, Corning), 20 ng/ml rhEGF (Peprotech), 400 ng/ml hydrocortisone (Sigma-Aldrich), 5 g/ml insulin (Sigma-Aldrich), 50 mg/ml Nystatin (Sigma-Aldrich), antibiotic-antimycotic (GIBCO) and amphotericin-B (Sigma-Aldrich).…”

Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

“…The immune-suppressive effects of MDSCs are relatively well-studied in mouse tumour models 82–85 and in patients with cancer 73,86–88 . Interestingly, recent studies demonstrate that MDSCs endow cancer cells with stem cell-like properties and are linked with cancer stemness 73,86–88 . Monocytic MDSCs (macrophages) can be recruited into the tumour microenvironment by CCL2 (REFS 74,89).…”

“…Furthermore, CCL2 and CCL5 can promote cancer cell proliferation, survival, motility 99 , epithelial–mesenchymal transition (EMT) and stemness 100–103 . In addition, these chemokines recruit MDSCs and macrophages into the tumour microenvironment, and in turn, promote and sustain human cancer stemness 73,86,88,104 .…”