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幽门螺杆菌感染促胃癌免疫逃逸分子机制及其干预的研究

项目来源

国家自然科学基金(NSFC)

项目主持人

魏道严

项目受资助机构

安徽医科大学

立项年度

2017

立项时间

未公开

项目编号

81772584

研究期限

未知 / 未知

项目级别

国家级

受资助金额

53.00万元

学科

医学科学-肿瘤学-消化系统肿瘤

学科代码

H-H16-H1617

基金类别

面上项目

关键词

胃癌 ; 幽门螺杆菌 ; KLF4 ; 肿瘤免疫逃逸 ; 分子机制 ; gastric cancer ; Helicobacter Pylori ; immune escape ; molecular mechanism

参与者

未公开

参与机构

未公开

项目标书摘要：近年来肿瘤免疫治疗为胃癌患者带来了新的希望，但对于胃癌逃逸免疫监视的分子机制知之甚少。已知幽门螺杆菌HP感染是诱发胃癌发生，诱导肿瘤免疫逃逸和促进胃癌恶化的主因，而机体抗HP感染免疫反应伴随产生的大量细胞因子CXCL8和IFN-γ发挥重要作用。我们之前发现:HP感染可引起抑癌基因KLF4表达降低或失活,KLF4与胃癌的发生发展预后关系密切，也对CXCL8和IFN-γ诱导的PD-L1表达有负调控作用。据此，我们提出科学假说:HP感染导致KLF4表达降低或失活，引起CXCL8和 PD-L1表达增加，产生局部免疫抑制微环境，促进肿瘤细胞免疫逃逸；靶向活化KLF4表达的药物可提高胃癌免疫治疗效果。本课题从细胞分子生物学阐明KLF4 对PD-L1和 CXCL8的调控作用及其分子机制；用胃癌组织标本进行相关性分析验证；用动物实验观察活化KLF4表达药物与免疫检查点阻断剂联合应用的抗胃癌治疗效果。

Application Abstract: The rapid development of tumor immunotherapy has brought new hope for patients with gastric cancer in recent years,however,little is known about the molecular mechanisms underlying gastric cancer escaping from immune surveillance.It has been shown that Helicobacter pylori(HP)infection is the main cause of gastric cancer initiation,tumor immune escaping and progression,during which the large amount of cytokines CXCL8 and IFN-γ produced by host’s anti-HP infection immune response play an important role.In our previous and preliminary studies,we found that HP infection led to significant reduction or inactivation of KLF4 expression in gastric epithelial or cancer cells,while loss of KLF4 expression had been shown to be closely related to initiation,development,progression,and worse prognosis of gastric cancer;KLF4 could negatively regulate CXCL8 promoter activity and the PD-L1 expression induced by IFN-γ treatment.Accordingly,we hypothesize that HP infection leads to decreased or inactivated KLF4 expression,causing increased CXCL8 and PD-L1 expression,resulting in local immunosuppressive microenvironment and promoting tumor cell immune escape;drugs that targeted activation of KLF4 expression will improve the therapeutic efficacy on gastric cancer when in combination with immunotherapy.The aims of this study are to elucidate the regulatory and mechanistic action of KLF4 on PDL-1 and CXCL8 expression;to examine the expression patterns of KLF4,PDL-1,and CXCL8 in human gastric tissue samples and their correlations with patient clinical related data;and to test the therapeutic efficacy on gastric cancer by using KLF4 activating drug in combination with immune checkpoint inhibitor in preclinical mouse model.It is anticipate that the results from this study will provide not only new insight into our further understanding the molecular mechanisms by which gastric cancer cells escape immune surveillance but also novel,mechanism-based immune therapeutic strategies to improve the outcome of patients with gastric cancer.

项目受资助省

安徽省

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  • 1.H. pylori infection induces CXCL8 expression and promotes gastric cancer progress through downregulating KLF4

    • 关键词：
    • CagA; CXCL8; gastric cancer; Helicobacter; pylori (H; pylori); Krüppel‐ like factor 4 (KLF4);SUPPRESSOR-CELLS; HELICOBACTER-PYLORI; CHECKPOINT BLOCKADE;INTERLEUKIN-8; AXIS; MICROENVIRONMENT; PROLIFERATION; METASTASIS;CHEMOKINES; LINEAGE
    • Liu, Zhengxia;Wu, Xiao;Tian, Yuanyuan;Zhang, Wanchun;Qiao, Siyuan;Xu, Wenting;Liu, Yakun;Wang, Siying
    • 《MOLECULAR CARCINOGENESIS》
    • 2021年
    • 60卷
    • 8期
    • 期刊

    Tumour-derived CXCL8 facilitates the movement of myeloid-derived suppressor cells, which are able to restrain antitumour immune responses to the tumour microenvironment. Kruppel-like factor 4 (KLF4) is a potential tumour suppressor in gastric cancer (GC). However, knowledge regarding correlations between KLF4 and CXCL8 in GC is limited. We use cellular and molecular biological methods to assess whether these two factors interact in GC. Expression CXCL8 and KLF4 was altered in human GC tissues compared to normal gastric tissues in opposite ways. Additionally, cytotoxin-associated gene A protein (CagA) gene transduction or Helicobacter pylori (H. pylori) infection upregulated CXCL8 expression. Knockdown of KLF4 expression increased CXCL8 protein and RNA expression, whereas its overexpression had the opposite effect. CXCL8-mediated enhancement of GC cell migration and proliferation was reversed by upregulation of KLF4 expression. Further mechanistic research revealed that KLF4 binds the CXCL8 promoter, suppressing CXCL8 transcription. Moreover, CXCL8 stimulation reduced KLF4 protein expression and promoted GC cell proliferation and migration, eventually promoting neoplasm growth in vivo. Together, our findings demonstrate that CagA promotes CXCL8 and inhibits KLF4. CXCL8 is a decisive downstream target gene of KLF4, and KLF4 negatively regulates CXCL8 in GC. Furthermore, CXCL8's negative regulation of KLF4 in vivo and in vitro, indicates that CagA may downregulate KLF4 by inducing CXCL8 expression, low expression of KLF4 further promotes that of CXCL8, forming a vicious circle in GC. Targeted KLF4 activation might improve the immunosuppressive microenvironment through direct negative regulation of CXCL8, providing a new potential target to strengthen the efficacy of immunotherapy in GC patients.

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