Activated neutrophils polarize protumorigenic interleukin-17A-producing T helper subsets through TNF-α-B7-H2-dependent pathway in human gastric cancer.
Activated neutrophils polarize protumorigenic interleukin-17A-producing T helper subsets through TNF-α-B7-H2-dependent pathway in human gastric cancer.
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在人胃癌中，激活的中性粒细胞通过 TNF-α-B7-H2 依赖性途径极化促肿瘤生成白细胞介素 17A 的 T 辅助细胞亚群
DOI：
10.1002/ctm2.484
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发表时间：
2021-06
影响因子：
10.6
通讯作者：
Zhuang Y
中科院分区：
文献类型：
--
作者：
Shan ZG;Chen J;Liu JS;Zhang JY;Wang TT;Teng YS;Mao FY;Cheng P;Zou QM;Zhou WY;Peng LS;Zhao YL;Zhuang Y
中性粒细胞是胃癌炎性组织中的重要细胞成分，但其在炎症性辅助性T细胞亚群发病机制中的作用尚不清楚。采用流式细胞术和免疫组化方法分析51例胃癌患者不同标本中中性粒细胞的反应和表型。通过对数秩检验和考克斯比例风险模型，使用Kaplan-Meier图和多变量分析进行患者生存期分析。纯化并培养中性粒细胞和CD 4 + T细胞用于离体、体外和体内调节和功能测定。GC患者表现出肿瘤中性粒细胞浸润增加，GC进展和患者预后不良。肿瘤内中性粒细胞通过CXCL 6/CXCL 8-CXCR 1介导的趋化作用在GC肿瘤中聚集，并表达活化分子CD 54和协同信号分子B7-H2。肿瘤诱导的中性粒细胞以剂量和时间依赖性方式强烈表达CD 54和B7-H2，并且肿瘤内中性粒细胞上CD 54和B7-H2的表达之间存在密切相关性。肿瘤源性肿瘤坏死因子-α（TNF-α）通过ERK-NF-κB通路促进中性粒细胞活化和中性粒细胞B7-H2表达，肿瘤组织中TNF-α水平与CD 54+或B7-H2+中性粒细胞显著相关。肿瘤浸润性和肿瘤条件化中性粒细胞通过B7-H2依赖性方式在体外有效诱导产生IL-17 A的Th亚群极化，这些极化的产生IL-17 A的Th细胞在体外通过炎症分子IL-17 A促进GC肿瘤细胞增殖，从而发挥促肿瘤作用，促进体内人GC的进展;当IL-17 A被阻断时，这些作用可以逆转。此外，肿瘤中B7-H2+中性粒细胞和IL-17 A的增加与晚期GC进展密切相关，并预测患者生存率较差。我们阐明了TNF-α激活的中性粒细胞将B7-H2与人GC中产生促肿瘤性IL-17 A的Th亚群极化联系起来的新的潜在机制。阻断这种病理性TNF-α-B7-H2-IL-17 A通路可能是治疗GC的有效治疗策略。我们的研究结果阐明了一种新的机制，即TNF-α激活的中性粒细胞将B7-H2与人GC中产生促肿瘤性IL-17 A的Th亚群极化联系起来。阻断这种病理性TNF-α-B7-H2-IL-17 A通路可能是治疗GC的有效治疗策略。
Neutrophils constitute massive cellular constituents in inflammatory human gastric cancer (GC) tissues, but their roles in pathogenesis of inflammatory T helper (Th) subsets are still unknown. Flow cytometry analysis and immunohistochemistry were used to analyze the responses and phenotypes of neutrophils in different samples from 51 patients with GC. Kaplan‐Meier plots and Multivariate analysis for the survival of patients were used by log‐rank tests and Cox proportional hazards models. Neutrophils and CD4+ T cells were purified and cultured for ex vivo, in vitro and in vivo regulation and function assays. GC patients exhibited increased tumoral neutrophil infiltration with GC progression and poor patient prognosis. Intratumoral neutrophils accumulated in GC tumors via CXCL6/CXCL8‐CXCR1‐mediated chemotaxis, and expressed activated molecule CD54 and co‐signaling molecule B7‐H2. Neutrophils induced by tumors strongly expressed CD54 and B7‐H2 in both dose‐ and time‐dependent manners, and a close correlation was obtained between the expressions of CD54 and B7‐H2 on intratumoral neutrophils. Tumor‐derived tumor necrosis factor‐α (TNF‐α) promoted neutrophil activation and neutrophil B7‐H2 expression through ERK‐NF‐κB pathway, and a significant correlation was found between the levels of TNF‐α and CD54+ or B7‐H2+ neutrophils in tumor tissues. Tumor‐infiltrating and tumor‐conditioned neutrophils effectively induced IL‐17A‐producing Th subset polarization through a B7‐H2‐dependent manner ex vivo and these polarized IL‐17A‐producing Th cells exerted protumorigenic roles by promoting GC tumor cell proliferation via inflammatory molecule IL‐17A in vitro, which promoted the progression of human GC in vivo; these effects could be reversed when IL‐17A is blocked. Moreover, increased B7‐H2+ neutrophils and IL‐17A in tumors were closely related to advanced GC progression and predicted poor patient survival. We illuminate novel underlying mechanisms that TNF‐α‐activated neutrophils link B7‐H2 to protumorigenic IL‐17A‐producing Th subset polarization in human GC. Blocking this pathological TNF‐α‐B7‐H2‐IL‐17A pathway may be useful therapeutic strategies for treating GC. Our results illuminate a novel mechanism that TNF‐α‐activated neutrophils link B7‐H2 to protumorigenic IL‐17A‐producing Th subset polarization in human GC. Blocking this pathological TNF‐α‐B7‐H2‐IL‐17A pathway may be useful therapeutic strategies for treating GC.
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DOI：
10.4049/jimmunol.1300524
发表时间：
2013-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lina TT;Pinchuk IV;House J;Yamaoka Y;Graham DY;Beswick EJ;Reyes VE
通讯作者：
Reyes VE
DOI：
10.1073/pnas.092576699
发表时间：
2002-04-30
影响因子：
11.1
作者：
Khayyamian, S;Hutloff, A;Mages, HW
通讯作者：
Mages, HW
影响因子：
20.3
作者：
Kryczek, Ilona;Banerjee, Mousumi;Zou, Weiping
通讯作者：
Zou, Weiping
人类癌症中新的 B7 家族检查点。
影响因子：
5.7
作者：
Ni L;Dong C
通讯作者：
Dong C
影响因子：
4.4
作者：
Godaly, G;Hang, L;Svanborg, C
通讯作者：
Svanborg, C