5-fluorouracil-induced up-regulation of exosomal PD-L1 causing immunosuppression in gastric cancer patients

Background: Although 5-fluorouracil chemotherapy has been thought to directly kill cancer cells and even play an immunostimulatory role, accumulating evidence indicates 5-fluorouracil also damages function of T cells through up-regulating programmed death-1-ligand 1(PD-L1), which is a negative regulator of T cell immune ability. Previous study has shown that PD-L1 has exosomal forms secreted in the microenvironment, except for membrane bound forms and extracellular soluble forms. In addition, exosomal PD-L1 retains stronger immunosuppressive activity. However, whether 5-fluorouracil can change the expression of exosomal PD-L1 and induce immunosuppression is unknown. Methods: We retrospectively detected exosomal PD-L1, by ELISA, in 17 stage III/IV gastric cancer patients before and after 2,4,6,8 repeated cycles of 5-fluorouracil chemotherapy treatment. Results: Compared with the expression at baseline, exosomal PD-L1 was up-regulated gradually in the plasma of patients when 2,4,6,8 repeated cycles of 5-fluorouracil were administered, accompanied with the decreased amounts of CD4+ and CD8+ T cells. Mechanistically, 5-fluorouracil up-regulated PD-L1 and exosomal PD-L1 in gastric cancer cell lines. Moreover, exosomal PD-L1 derived from gastric cancer cells induced apoptosis of T cells after 48h treatment, which could be reversed by nivolumab. Conclusions: 5-Fluorouracil up-regulated exosomal PD-L1 which induced apoptosis of T cells and caused immunosuppression in gastric cancer patients. Legal entity responsible for the study: Academic Group. Funding: National Natural Science Foundation of China. Disclosure: All authors have declared no conflicts of interest.