Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

Emerging evidence indicates a link between the increased proportion of regulatory T cells (T-regs) and reduced survival in patients who have been diagnosed with cancer. Cancer stem cells (CSCs) have been indicated to play a vital role in tumour initiation, drug resistance and recurrence. However, the relationship between T-regs and CSCs remains largely unknown. Here, we sorted out ovarian cancer stem-like side population (SP) cells and CD133(+) cells to investigate the influence of ovarian CSCs on T-regs. Among the various immune-related molecules that we assessed, C-C motif chemokine ligand 5 (CCL5) was the most elevated in ovarian CSCs relative to that in the non-CSCs. The expression of its receptor, C-C motif chemokine receptor 5 (CCR5), was also increased on the surface of T-regs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit T-regs via CCL5-CCR5 interactions. We further assessed the expression of interleukin (IL)-10 in T-regs cultured with different cancer cells. T-regs cultured in conditioned medium (CM) from ovarian CD133(+) cells expressed a higher level of IL-10 than T-regs cultured in CM from CD133(-) cells, indicating that T-regs exert pronounced immune-inhibitory functions in CSC-rich environments. Furthermore, co-culture with ovarian cancer cell lines induced the expression of matrix metalloproteinase-9 (MMP9) in T-regs which, in turn, enhanced the degradation of the extracellular matrix and enabled the invasion of tumour cells, thereby facilitating tumour metastasis. For the first time, to our knowledge, our findings describe the relationship between ovarian CSCs and T-regs, and demonstrated that these two cell populations co-operate to promote tumour immune tolerance and enhance tumour progression.