Breast Cancer Cell–Derived GM-CSF Licenses Regulatory Th2 Induction by Plasmacytoid Predendritic Cells in Aggressive Disease Subtypes

Abstract

Reciprocal interactions between tumor cells and their microenvironment vitally impact tumor progression. In this study, we show that GM-CSF produced by primary breast tumor cells induced the activation of plasmacytoid predendritic cells (pDC), a cell type critical to anti-viral immunity. pDC that expressed the GM-CSF receptor were increased in breast tumors compared with noninvolved adjacent breast tissue. Tumoractivated pDC acquired na€ ve CD4 þ T-cell stimulatory capacity and promoted a regulatory Th2 response. Finally, the concomitant increase of GM-CSF and pDC was significantly associated with relatively more aggressive breast cancer subtypes. Our results characterize the first tumor-derived factor that can activate pDC to promote a regulatory Th2 response, with implications for therapeutic targeting of a tumor-immune axis of growing recognition in its significance to cancer. CancerRes; 75(14); 2775-87. Ó2015 AACR.

Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis

“…17, 18 The levels of GM-CSF were found to increase in cancer patients, which induced accumulation of MDSCs. 19, 20, 21 We therefore treated bone marrow cells from Balb/c mice with 20 ng/ml of GM-CSF for 5 days and found that more than 70% of Balb/c bone marrow CD11b + CD11c − cells were Ly6G hi gMDSCs and <10% of them were Ly6C hi mMDSCs (Figure 3b). The ratio of the GM-CSF-induced mMDSCs and gMDSCs out from the bone marrow culture was similar to the ratio of them in the bone marrow and spleen of tumor-bearing mice in our study (Figure 1d) and in other breast cancer mouse model.…”

Human dendritic cell subsets: an update

“…Conflicting roles for pDC have been reported in allergy . Tolerogenic pDC under the influence of GM‐CSF have also been proposed to contribute to tumour progression …”

State-of-the-art of regulatory dendritic cells in cancer

“…They have been found to promote immunosuppression by enhancing IL-10 secretion by CD4 + Foxp3 − T cells in human hepatocarcinoma (Pedroza-Gonzalez, et al, 2015), while their presence is associated with regulatory Th2 responses in breast cancer patients (Ghirelli, et al, 2015) and human melanoma (Aspord, Leccia, Charles, & Plumas, 2013), as well as Treg activity in human breast cancer (Sisirak, et al, 2013). Finally, plasmacytoid DCs contribute to tumor-induced immunosuppression by inducing CD8 + regulatory T cells in the human ovarian cancer microenvironment (Wei, et al, 2005).…”