Immunotherapy based on BCG vaccination is an effective treatment in bladder cancer, but a positive response is restricted to a subset of patients and for a limited period of time only. This suggests that T cells antitumor responses are effective but can become compromised in bladder cancer. To investigate the underlying mechanisms, we first identified peripheral blood monocytes and tumor macrophages using the pan-monocyte/macrophage marker CD14, and found that the PD-L1 expression on the monocytes/macrophages in bladder cancer patients was significantly higher than that in controls. The monocytes from bladder cancer patients were also more capable at inducing apoptosis and inhibiting proliferation in activated autologous T cells, than monocytes from controls, which was directly associated with the level of PD-L1 expression. We next investigated the tumor cells' participation in upregulating PD-L1 in monocytes/macrophages. Significant elevation of PD-L1 was observed in monocytes after culturing with autologous tumor cells, which did not require direct contact but required soluble factors. The STAT phosphorylation pattern in monocytes after tumor cell coculture was consistent with effects of the interleukin (IL)-10 signaling pathway. We then found that removal of IL-10 in monocyte-tumor cell coculture reduced the PD-L1 upregulation in monocytes, but IL-10 by itself was unable to directly upregulate PD-L1. Primary bladder tumor cells secreted significant levels of IL-10, indicating that they could serve as the source of IL-10. Together, these results demonstrated a novel pathway that bladder cancer cells induced immunosuppression of T cells by supporting PD-L1 expression in tumor macrophages partially through IL-10.
Cell biology international. 2016 Dec 17 [Epub ahead of print]
Xingyuan Wang, Shaobin Ni, Qiyin Chen, Li Ma, Zhixing Jiao, Chunyang Wang, Guang Jia
Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.