Combinational blockade of MET and PD-L1 improves pancreatic cancer immunotherapeutic efficacy.
Combinational blockade of MET and PD-L1 improves pancreatic cancer immunotherapeutic efficacy.
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MET 和 PD-L1 联合阻断可提高胰腺癌免疫治疗效果
DOI：
10.1186/s13046-021-02055-w
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发表时间：
2021-09-03
期刊：
影响因子：
--
通讯作者：
Liang T
中科院分区：
文献类型：
--
作者：
Li E;Huang X;Zhang G;Liang T
研究背景受体酪氨酸激酶（receptor tyrosine kinases，RTKs）的表达和激活异常与多种人类肿瘤相关。然而，目前的RTK靶向策略对胰腺癌这种具有复杂免疫微环境的高度恶性肿瘤几乎没有影响。鉴于胰腺癌的免疫治疗仍然具有挑战性，本研究旨在阐明RTKs在胰腺肿瘤中的预后作用与不同的免疫学背景，并探讨其在胰腺癌immunotherapy.MethodsKaplan-Meier曲线的靶向潜力被用来分析的预后意义的所有已知的RTKs迄今在免疫“热”和“冷”胰腺癌。应用基因表达谱交互分析软件（Gene Expression Profiling Interactive Analysis-2）分析RTKs在胰腺肿瘤和正常胰腺组织中的差异表达及其与免疫检查点（immune checkpoint，ICP）的相关性。收集150例胰腺癌内部临床组织标本，通过免疫组织化学分析进行表达和相关性验证。采用两种胰腺癌细胞系，通过生物化学和流式细胞术证明RTK对ICP的调节作用。联合应用两个携带胰腺肿瘤的活体模型，研究RTK抑制和免疫检查点阻断联合方案用于胰腺癌免疫治疗。结果MET被确定为胰腺癌特异性RTK，其与免疫“热”和“冷”胰腺癌的预后显着相关。MET在胰腺癌组织中高度上调，并与PD-L1水平呈正相关。MET和PD-L1表达升高与胰腺癌的淋巴结转移、肿瘤TNM分期和总生存期密切相关。从机制上讲，MET可以与PD-L1相互作用，并以多种方式维持其表达水平。发现MET缺乏促进淋巴细胞浸润到胰腺肿瘤中。最后，在原位和皮下胰腺癌小鼠模型中验证了MET抑制与PD-1/PD-L1阻断相结合的显著益处。结论本研究系统地研究了一种新型胰腺癌免疫治疗的潜在有效性，靶向RTKs，并揭示了MET在PD-L1调节中的功能以及MET和PD-L1在胰腺癌中的联合治疗效果。
BackgroundDysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers. However, current RTK-targeting strategies exert little effect on pancreatic cancer, a highly malignant tumor with complex immune microenvironment. Given that immunotherapy for pancreatic cancer still remains challenging, this study aimed to elucidate the prognostic role of RTKs in pancreatic tumors with different immunological backgrounds and investigate their targeting potential in pancreatic cancer immunotherapy.MethodsKaplan–Meier plotter was used to analyze the prognostic significance of each of the all-known RTKs to date in immune “hot” and “cold” pancreatic cancers. Gene Expression Profiling Interactive Analysis-2 was applied to assess the differential expression of RTKs between pancreatic tumors and normal pancreatic tissues, as well as its correlation with immune checkpoints (ICPs). One hundred and fifty in-house clinical tissue specimens of pancreatic cancer were collected for expression and correlation validation via immunohistochemical analysis. Two pancreatic cancer cell lines were used to demonstrate the regulatory effects of RTKs on ICPs by biochemistry and flow cytometry. Twoin vivomodels bearing pancreatic tumors were jointly applied to investigate the combinational regimen of RTK inhibition and immune checkpoint blockade for pancreatic cancer immunotherapy.ResultsMET was identified as a pancreatic cancer-specific RTK, which is significantly associated with prognosis in both immune “hot” and “cold” pancreatic cancers. MET was observed to be highly upregulated in pancreatic cancer tissues, and positively correlated with PD-L1 levels. Elevated MET and PD-L1 expressions were closely associated with lymph node metastasis, tumor TNM stage, and overall survival in pancreatic cancer. Mechanistically, MET could interact with PD-L1, and maintain its expression level in multiple ways. MET deficiency was found to facilitate lymphocyte infiltration into pancreatic tumors. Finally, significant benefits of combining MET inhibition with PD-1/PD-L1 blockage were verified in both orthotopic and subcutaneous mouse models of pancreatic cancer.ConclusionsThis study systematically investigated the potential effectiveness of a novel pancreatic cancer immunotherapy targeting RTKs, and revealed the function of MET in PD-L1 regulation as well as the combined therapeutic efficacy of MET and PD-L1 in pancreatic cancer.
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影响因子：
37.3
作者：
Du Z;Lovly CM
通讯作者：
Lovly CM
影响因子：
3.5
作者：
Lee, SJ;Jang, BC;Choi, IH
通讯作者：
Choi, IH
影响因子：
8.8
作者：
Abiko, K.;Matsumura, N.;Hamanishi, J.;Horikawa, N.;Murakami, R.;Yamaguchi, K.;Yoshioka, Y.;Baba, T.;Konishi, I.;Mandai, M.
通讯作者：
Mandai, M.
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA
影响因子：
32.4
作者：
Butte, Manish J.;Keir, Mary E.;Freeman, Gordon J.
通讯作者：
Freeman, Gordon J.