5-FU-Induced Upregulation of Exosomal PD-L1 Causes Immunosuppression in Advanced Gastric Cancer Patients
Min Zhang, Yibo Fan, Xiaofang Che, Kezuo Hou, Chaoxu Zhang, Ce Li, Ti Wen, Shuo Wang, Yu Cheng, Yunpeng Liu, Xiujuan Qu
Abstract
Although the cytotoxic chemotherapeutic agent 5-fluorouracil (5-FU) is generally considered to directly kill cancer cells and exert immunostimulatory effects in advanced gastric cancer, accumulating evidence indicates that it upregulates the expression of PD-L1, a representative immune checkpoint blockade molecule involved in negative regulation of the immune response. It was reported that exosomes could transfer functional PD-L1 locally and distantly to suppress the antitumor immune response. However, whether 5-FU alters the expression of exosomal PD-L1 and induces immunosuppression in gastric cancer remains unclear. Herein, we found that 5-FU increased gastric cancer-derived exosomal PD-L1. Importantly, compared with baseline levels, circulating exosomal PD-L1 was significantly upregulated in 21 stage Ⅲ-Ⅳ gastric cancer patients after 2, 4 and 6 repeated cycles of fluoropyrimidine treatment (P=0.009, P=0.047 and P=0.023, respectively), accompanied by decreased amounts of IFN-γ, TNF-α, IL-2, IL-6 and GM-CSF (P=0.014, P=0.004, P=0.009, P=0.031 and P=0.014, respectively). Additionally, circulating exosomal PD-L1 was increased more significantly in clinical non-responders compared with responders (P=0.018). Furthermore, exosomal PD-L1 induced apoptosis in Jurkat T cells and inhibited T cells activation in PBMCs, which could be partly reversed by nivolumab. These results suggested that 5-FU-induced upregulation of exosomal PD-L1 causes systemic immunosuppression in advanced gastric cancer following multiple cycles of chemotherapy, especially after 2 cycles.