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 two, four, and six 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 cell 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 two cycles.
Highlights
Gastric cancer (GC) is the fifth most prevalent cancer and the third leading cause of cancer-related death worldwide
Aliquots (2 × 105) of peripheral blood mononuclear cells (PBMCs) were placed in wells of 96well-plates, and T cells in PBMCs were activated by human CD3/CD28 T cell activator (#10971, Stemcell Technologies) for 6 h at 37◦C and coincubated with MKN74-derived negative control (NC) exosomes or programmed death-ligand 1 (PD-L1)-KD exosomes for 48 h in the presence or absence of nivolumab (Bristol-Myers Squibb Company, Princeton, NJ, USA)
Immunotherapy, which is characterized by immune checkpoint blockade (ICB), has changed the standard of care for a subgroup of patients and improved survival compared with previous criteria in several cancer types, even though limitations remain [31, 32]
Summary
Gastric cancer (GC) is the fifth most prevalent cancer and the third leading cause of cancer-related death worldwide. In 2018, GC caused 782,685 deaths [1]. Accumulating evidence indicates that, conventional chemotherapeutic drugs exert direct cytostatic/cytotoxic effects [3], they could alter tumor-reactive. Immunosuppressive Effects of 5-FU in Gastric Cancer immune responses and even display immunosuppressive features [4], which may affect the survival of patients. 5-FU was shown to selectively eliminate tumor-associated MDSCs resulting in enhanced T-celldependent antitumor immunity in several types of cancer [7]. A better understanding of the mechanism by which 5-FU may alter antitumor immune responses in gastric cancer patients, especially immune status changes after different cycles of 5-FU treatment, is important for the improvement of treatment efficacy
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