Treg/Th17 polarization by distinct subsets of breast cancer cells is dictated by the interaction with mesenchymal stem cells.

Breast cancer (BC) cells (BCCs) exist within a hierarchy beginning with cancer stem cells (CSCs). Unsorted BCCs interact with mesenchymal stem cells (MSCs) to induce regulatory T cells (T_regs). This study investigated how distinct BCC subsets interacted with MSCs to polarize T-cell response, T_regs versus T helper 17 (Th17). This study tested BC initiating cells (CSCs) and the relatively more mature early and late BC progenitors. CSCs interacted with the highest avidity to MSCs. This interaction required CXCR4 and connexin 43 (Cx43)-dependant gap junctional intercellular communication (GJIC). This interaction induced T_reg whereas interactions between MSCs and the progenitors induced Th17 response. The increases in T_reg and Th17 depended on MSCs but not CTLA-4, which was increased in the presence of MSCs. Studies with BM stroma (fibroblasts) and MSCs from the same donors, indicated specific effects of MSCs. In total, MSC-CSC interaction required CXCR4 for GJIC. This led to increased T_regs and TGFβ, and decreased Th17. In contrast, late and early BCCs showed reduced formation of GJIC, decreased T_reg and increased Th17 and IL-17. These findings have significance to the methods by which CSCs evade the immune response. The findings could provide methods of intervention to reverse immune-mediated protection and support of BC.