Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer
Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer
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DOI：
10.1158/2326-6066.cir-17-0443
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发表时间：
2018-11-01
影响因子：
10.1
通讯作者：
Ryan, Aideen E.
中科院分区：
文献类型：
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作者：
O'Malley, Grace;Treacy, Oliver;Ryan, Aideen E.
间充质来源的基质细胞位于上皮室下方，并在肠道中提供结构支持。这些肠基质细胞与上皮细胞区室以及浸润的造血免疫细胞相互作用。这些细胞在炎症期间调节免疫稳态的重要性已得到广泛认可。然而，人们对它们在炎症肿瘤微环境中的功能和表型知之甚少。使用结直肠癌的同基因免疫原性模型，我们发现 CT26 结直肠癌细胞中 TNFa 启动的炎症信号选择性诱导基质细胞中 PD-L1 的表达。利用CD274 shRNA和抗体介导的方法，我们发现基质细胞PD-L1可增强免疫抑制作用，其特征是在体外抑制活化的CD8(+)颗粒酶B分泌T细胞，并且CD8(+)效应细胞的抑制与增强的肿瘤进展相关。体内给予抗PD-1可以逆转基质细胞的免疫抑制和肿瘤促进作用。我们在两组临床样本中验证了基质细胞 CD274 表达的结果，并观察了人类基质细胞对暴露于人类结肠癌细胞炎症分泌组的反应中的 PD-L1 诱导，无论微卫星不稳定性如何。总的来说，我们的数据表明，肿瘤相关基质细胞通过 PD-L1 诱导支持 T 细胞抑制，这依赖于结肠癌炎症信号传导。我们的研究结果揭示了间充质基质细胞 PD-L1 在抑制 CD8(+) 抗肿瘤免疫反应和增强结直肠癌进展中的关键作用。 (C) 2018 年 AACR。
Stromal cells of mesenchymal origin reside below the epithelial compartment and provide structural support in the intestine. These intestinal stromal cells interact with both the epithelial cell compartments, as well as infiltrating hematopoietic immune cells. The importance of these cells in regulating immune homeostasis during inflammation is well recognized. However, little is known about their function and phenotype in the inflammatory tumor microenvironment. Using a syngeneic, immunogenic model of colorectal cancer, we showed that TNFa-initiated inflammatory signaling in CT26 colorectal cancer cells selectively induced PD-L1 expression in stromal cells. Using CD274 shRNA and antibodymediated approaches, we showed that stromal cell PD-L1 potentiated enhanced immunosuppression, characterized by inhibition of activated CD8(+) granzyme B-secreting T cells in vitro, and the inhibition of CD8(+) effector cells was associated with enhanced tumor progression. Stromal cell immunosuppressive and tumor-promoting effects could be reversed with administration of anti-PD-1 in vivo. We validated our findings of stromal cell CD274 expression in two cohorts of clinical samples and also observed PD-L1 induction on human stromal cells in response to exposure to the inflammatory secretome fromhuman colon cancer cells, irrespective of microsatellite instability. Collectively, our data showed that tumor-associated stromal cells support T-cell suppression by PD-L1 induction, which is dependent on colon cancer inflammatory signaling. Our findings reveal a key role of mesenchymal stromal cells PD-L1 in suppression of CD8(+) antitumor immune responses and potentiation of colorectal cancer progression. (C) 2018 AACR.