Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction

Abstract

Myeloid-derived suppressor cells (MDSCs), identified as Gr1+CD11b+ cells in mice, expand during cancer and promote tumor growth, recurrence and burden. However, little is known about their role in bone metastases. We hypothesized that MDSCs may contribute to tumor-induced bone disease, and inoculated breast cancer cells into the left cardiac ventricle of nude mice. Disease progression was monitored weekly by X-ray and fluorescence imaging and MDSCs expansion by fluorescence-activated cell sorting. To explore the contribution of MDSCs to bone metastasis, we co-injected mice with tumor cells or PBS into the left cardiac ventricle and Gr1+CD11b+ cells isolated from healthy or tumor-bearing mice into the left tibia. MDSCs didn’t induce bone resorption in normal mice, but increased resorption and tumor burden significantly in tumor-bearing mice. In vitro experiments showed that Gr1+CD11b+ cells isolated from normal and tumor-bearing mice differentiate into osteoclasts when cultured with RANK ligand and macrophage colony-stimulating factor, and that MDSCs from tumor-bearing mice upregulate parathyroid hormone-related protein (PTHrP) mRNA levels in cancer cells. PTHrP upregulation is likely due to the 2-fold increase in transforming growth factor β expression that we observed in MDSCs isolated from tumor-bearing mice. Importantly, using MDSCs isolated from GFP-expressing animals, we found that MDSCs differentiate into osteoclast-like cells in tumor-bearing mice as evidenced by the presence of GFP+TRAP+ cells. These results demonstrate that MDSCs expand in breast cancer bone metastases and induce bone destruction. Furthermore, our data strongly suggest that MDSCs are able to differentiate into osteoclasts in vivo and that this is stimulated in the presence of tumors.

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

“…It has been previously shown that MDSC populations expand in athymic mice bearing TNBC xenografts, specifically MDA-MB-231, during tumor development (26). The chemotactic role of IL-8 toward immune cell populations includes the ability of this chemokine to recruit MDSCs to the tumor microenvironment (27,28).…”

“…Interestingly, different mechanisms appear to be used by the two subgroups of MDSCs, with M-MDSCs mediating immune suppression via expression of high levels of ARG-1 and iNOS and PMN-MDSCs mainly producing high levels of ROS (60). While initially characterized in mouse cancer models (61), expansion of MDSCs is known to take place in many solid tumor types, including breast cancer (26), and high numbers of MDSCs are detected in the peripheral blood of cancer patients, particularly in advanced stages of disease, compared with blood of healthy donors (62). The study of the mechanisms involved in the tumor recruitment of MDSCs has led to the understanding that homing of M-MDSCs is mainly dependent upon the activation of the CCL2/CCR2 axis, while attraction of PMN-MDSCs has been mostly associated with signaling via the CXCR2 receptor, which is in agreement with the predominant expression of CXCR1 and CXCR2 in PMN-MDSCs, as compared with the prevalence of CCR2 expression in M-MDSC populations (63).…”

A multidisciplinary study usingin vivotumor models and microfluidic cell-on-chip approach to explore the cross-talk between cancer and immune cells

“…In contrast, MDSC were present at a higher frequency in IRF-8 KO tumorbearing mice. These cells have been identified as important indicators of conditions that favor tumor growth (Danilin et al, 2012;Gabrilovich et al, 2012). Interestingly, IRF-8 was recently shown to be directly involved in MDSC development (Waight et al, 2013); these findings are of extreme relevance, as they provide support for a possibility that IRF-8 might orchestrate chemokine-chemokine receptor patterns in the tumor microenvironment and so modulate immune cell infiltration.…”

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

“…24,25 Mouse MDSC consist of a heterogeneous population distinct from immature myeloid cells present in tumor-free mice. Two main MDSC subsets have been described: the monocytic subset (mMDSC, CD11b…”