FasL(+) PD-L2(+) Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression.
FasL(+) PD-L2(+) Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression.
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FasL( )PD-L2( ) 鉴定出人类胃癌中一种新型免疫抑制性中性粒细胞群，可促进疾病进展
DOI：
10.1002/advs.202103543
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Zhuang Y
中科院分区：
文献类型：
--
作者：
Shan ZG;Zhao YL;Zhang JY;Yan ZB;Wang TT;Mao FY;Teng YS;Peng LS;Chen WY;Wang P;Cheng P;Tian WQ;Chen J;Chen W;Zhuang Y
中性粒细胞是胃癌组织中丰富的细胞成分，但其在胃癌发生发展中的作用机制尚不清楚。在这里，发现GC患者在肿瘤中显示出显著更高的中性粒细胞浸润，这是由CXCL 12-CXCR 4趋化性调节的。这些肿瘤浸润性中性粒细胞表达高水平的免疫抑制分子FasL和PD-L2，这种具有独特表型的FasL+ PD-L2+中性粒细胞亚群占晚期GC中所有中性粒细胞的至少20%，并预测患者生存率差。肿瘤以时间依赖性和剂量依赖性方式诱导中性粒细胞表达FasL和PD-L2蛋白，其表型与GC肿瘤相似。从机制上讲，Th 17细胞来源的IL-17 A和肿瘤细胞来源的G-CSF可分别通过激活ERK-NF-κB和JAK-STAT 3信号通路显著诱导中性粒细胞FasL和PD-L2表达。重要的是，在过度表达FasL和PD-L2后，中性粒细胞获得对肿瘤特异性CD 8 + T细胞的免疫抑制功能，并在体外和体内促进人GC肿瘤的生长和进展，这可以通过阻断这些中性粒细胞上的FasL和PD-L2来逆转。因此，这项工作在GC中鉴定了一种新的促肿瘤性FasL+ PD-L2+中性粒细胞亚群，并为靶向这些致病细胞的人类癌症免疫抑制和抗癌治疗提供了新的见解。CXCL 12-CXCR 4趋化性介导中性粒细胞募集到胃癌（GC）环境中。Th 17细胞来源的IL-17 A和肿瘤细胞来源的G-CSF激活ERK-NF-κB和JAK-STAT 3信号通路，诱导中性粒细胞上的FasL和PD-L2表达。这些免疫抑制性FasL+ PD-L2+中性粒细胞通过以FasL/PD-L2依赖性方式抑制肿瘤特异性CD 8 + T细胞免疫来发挥促肿瘤发生作用。靶向这些病理性FasL+ PD-L2+中性粒细胞将改善GC治疗。
Neutrophils constitute abundant cellular components in human gastric cancer (GC) tissues, but their protumorigenic subset in pathogenesis of GC progression is unclear. Here, it is found that patients with GC show significantly higher neutrophil infiltration in tumors that is regulated by CXCL12‐CXCR4 chemotaxis. These tumor‐infiltrating neutrophils express high level immunosuppressive molecules FasL and PD‐L2, and this FasL+PD‐L2+ neutrophil subset with a unique phenotype constitutes at least 20% of all neutrophils in advanced GC and predicts poor patient survival. Tumor induces neutrophils to express FasL and PD‐L2 proteins with similar phenotype to those in GC tumors in both time‐dependent and dose‐dependent manners. Mechanistically, Th17 cell‐derived IL‐17A and tumor cell‐derived G‐CSF can significantly induce neutrophil FasL and PD‐L2 expression via activating ERK‐NF‐κB and JAK‐STAT3 signaling pathway, respectively. Importantly, upon over‐expressing FasL and PD‐L2, neutrophils acquire immunosuppressive functions on tumor‐specific CD8+ T‐cells and promote the growth and progression of human GC tumors in vitro and in vivo, which can be reversed by blocking FasL and PD‐L2 on these neutrophils. Thus, the work identifies a novel protumorigenic FasL+PD‐L2+ neutrophil subset in GC and provides new insights for human cancer immunosuppression and anti‐cancer therapies targeting these pathogenic cells. CXCL12‐CXCR4 chemotaxis mediates the recruitment of neutrophils into gastric cancer (GC) environment. Th17 cell‐derived IL‐17A and tumor cell‐derived G‐CSF activate ERK‐NF‐κB and JAK‐STAT3 signaling pathways to induce FasL and PD‐L2 expression on neutrophils. These immunosuppressive FasL+PD‐L2+ neutrophils exert protumorigenic effects by suppressing tumor‐specific CD8+ T‐cell immunity in FasL/PD‐L2 dependent manners. Targeting these pathological FasL+PD‐L2+ neutrophils will improve GC treating.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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