PMN-MDSCs accumulation induced by CXCL1 promotes CD8+ T cells exhaustion in gastric cancer

Myeloid-derived suppressor cells (MDSCs) accumulation in multiple tumor is associated with immune checkpoint inhibitors (ICIs) resistance. However, mechanisms of MDSCs in ICIs resistance of gastric Cancer (GC) have not been thoroughly explored. In this study, we found that the PMN-MDSCs frequency rather than the M-MDSCs frequency was correlated with the survival of GC patients and CXCL1 induced PMN-MDSCs accumulation in GC. S100A8/A9 heterodimer, a hallmark of MDSCs, upregulated the CXCL1 expression in GC cells through the TLR4/p38 MAPK/NF-κB pathway. Notably, PMN-MDSCs exerted immunosuppressive effect through S100A8/A9. Mechanically, S100A8/A9 led to CD8⁺ T cells exhaustion including inhibiting CD8⁺ T cells glycolysis, proliferation and TNF-α and IFN-γ production, which was dependent on TLR4/Akt/mTOR pathway. In tumor-bearing mice, the CXCR2 Antagonist SB225002 decreased PMN-MDSCs accumulation, increased CD8⁺ T cells infiltration in GC and further enhanced anti-tumor efficacy of anti-PD-1. Taken together, our study identified that CXCL1 induced PMN-MDSCs accumulation in GC, and unveiled how PMN-MDSCs promoted CD8⁺ T cells exhaustion, which may provide a potential therapeutic strategy for GC.