PMN-MDSCs accumulation induced by CXCL1 promotes CD8+ T cells exhaustion in gastric cancer
PMN-MDSCs accumulation induced by CXCL1 promotes CD8+ T cells exhaustion in gastric cancer
复制标题
CXCL1诱导的PMN-MDSCs积累促进胃癌中CD8 T细胞耗竭
DOI：
10.1016/j.canlet.2022.215598
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发表时间：
2022
期刊：
影响因子：
9.7
通讯作者：
Jianbo Xu
中科院分区：
文献类型：
--
作者：
Xingyu Zhou;Deliang Fang;Haohan Liu;Xinde Ou;Chaoyue Zhang;Zirui Zhao;Shaoji Zhao;Jianjun Peng;Shirong Cai;Yulong He;Jianbo Xu
髓系来源的抑制细胞(MDSCs)在多发性肿瘤中的积聚与免疫检查点抑制物(ICIS)的抵抗有关。然而，MDSCs在胃癌ICIS耐药中的作用机制尚未深入研究。在本研究中，我们发现PMN-MDSCs频率而不是M-MDSCs频率与GC患者的生存相关，并且CXCL1诱导了PMN-MDSCs在GC中的积聚。作为MDSCs标志的S100A8/A9异源二聚体通过TLR4/p38MAPK/NF-κB途径上调GC细胞中CXCL1的表达。值得注意的是，PMN-MDSCs通过S100A8/A9发挥免疫抑制作用。S100A8/A9通过TLR4/AKT/mTOR途径抑制CD8+T细胞糖酵解、增殖及肿瘤坏死因子-α和干扰素-γ的产生，从而导致CD8+T细胞耗竭。在荷瘤小鼠中，CXCR2拮抗剂SB225002减少了PMN-MDSCs的聚集，增加了CD8+T细胞在GC中的浸润，进一步增强了抗PD-1的抗肿瘤作用。综上所述，我们的研究证实了CXCL1诱导了PMN-MDSCs在GC中的聚集，揭示了PMN-MDSCs是如何促进CD8+T细胞耗竭的，这可能为GC提供一种潜在的治疗策略。
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.