Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer.
Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer.
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DOI：
10.18632/oncotarget.26473
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发表时间：
2018-12-21
期刊：
影响因子：
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通讯作者：
Zavros, Yana
中科院分区：
文献类型：
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作者：
Chakrabarti, Jayati;Holokai, Loryn;Zavros, Yana
表达程序性细胞死亡配体1（PD-L1）的肿瘤细胞与CD 8+细胞毒性T淋巴细胞（CTL）上的PD-1相互作用，以抑制CTL效应器功能。在胃癌中，调节PD-L1的机制尚不清楚。Hedgehog（Hh）信号通路在包括胃癌在内的各种癌症中被重新激活。在这里，我们测试了Hh诱导的PD-L1灭活效应T细胞功能并允许胃癌细胞增殖的假设。小鼠类器官是从三重转基因小鼠模型的肿瘤中产生的，该模型经过改造，在表达Lgr 5的干细胞（mTGO）或正常小鼠胃（mGO）中表达活化的GLI 2等位基因GLI 2A。用从正常（mGOCM）或癌症（mTGOCM）类器官收集的条件培养基脉冲骨髓来源的树突状细胞（DC）。然后在PD-L1中和抗体（PD-L1 Ab）存在下，将脉冲DC和CTL与mT3或mT4共培养。人源性胃癌类器官（huTcR）用于药物和异种移植物测定。Hh/Gli抑制剂GANT-61在体内和体外均显著降低PD-L1的表达和肿瘤细胞增殖。PD-L1 Ab处理诱导mTGO/免疫细胞共培养物中的肿瘤细胞凋亡。GANT-61治疗使人肝癌细胞在体内和体外对标准治疗化疗药物敏感。因此，Hh信号传导介导胃癌细胞中的PD-L1表达，并随后促进肿瘤增殖。
Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation. Mouse organoids were generated from tumors of a triple-transgenic mouse model engineered to express an activated GLI2 allele, GLI2A, in Lgr5-expressing stem cells, (mTGOs) or normal mouse stomachs (mGOs). Bone marrow-derived dendritic cells (DCs) were pulsed with conditioned media collected from normal (mGOCM) or cancer (mTGOCM) organoids. Pulsed DCs and CTLs were then co-cultured with either mGOs or mTGOs in the presence of PD-L1 neutralizing antibody (PD-L1Ab). Human-derived gastric cancer organoids (huTGOs) were used in drug and xenograft assays. Hh/Gli inhibitor, GANT-61 significantly reduced the expression of PD-L1 and tumor cell proliferation both in vivo and in vitro. PD-L1Ab treatment induced tumor cell apoptosis in mTGO/immune cell co-cultures. GANT-61 treatment sensitized huTGOs to standard-of-care chemotherapeutic drugs both in vivo and in vitro. Thus, Hh signaling mediates PD-L1 expression in gastric cancer cells and subsequently promotes tumor proliferation.