Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, West Huaihai Road 241, Shanghai 200030, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Huashan Road 1954, Shanghai 200024, China.
Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, West Huaihai Road 241, Shanghai 200030, China.
Cell Immunol. 2022 Sep;379:104577. doi: 10.1016/j.cellimm.2022.104577. Epub 2022 Jul 9.
Variations in FGFR1 are common driver mutations of LSQCC. And immune checkpoint inhibitors targeting PD-1 and PD-L1 are powerful anticancer weapons. Activation of FGFR1 leads to tumorigenesis through multiple downstream molecules, including YAP, but whether and how FGFR1 regulates tumor immune evasion remain largely unclear.
LSQCC cells were modified to increase or decrease the expression of FGFR1, YAP and PD-L1, as assessed by molecular assays. After FGFR1 knockdown, cancer cells were assessed after cocultured with Jurkat T cells in vitro, and the tumor microenvironment were analyzed in C57BL/6 mice. The effect of the combination of FGFR1 knockdown and PD-1 blockade was also explored.
In human LSQCC, activation of FGFR1 was positively correlated with transcription of PD-L1. In H520 and HCC95 cells, FGFR1 upregulated PD-L1 expression via YAP, and YAP initiated the transcription of PD-L1 after binding to its promoter region. FGFR1 knockdown decreased tumor growth, reduced immune escape and induced reactivation of CD8+ T cells. The combination of FGFR1 knockdown and PD-1 blockade synergistically exerted antitumor effects.
The FGFR1/YAP/PD-L1 regulatory axis mediates tumor-associated immune suppression in lung squamous cell carcinoma, and FGFR1 knockdown reactivates T cells in the tumor microenvironment. Synergistic inhibition of both FGFR1 and PD-1/PD-L1 pathways may be a possible treatment for lung cancer patients.
FGFR1 变异是 LSQCC 的常见驱动突变。针对 PD-1 和 PD-L1 的免疫检查点抑制剂是强大的抗癌武器。FGFR1 的激活通过包括 YAP 在内的多个下游分子导致肿瘤发生，但 FGFR1 是否以及如何调节肿瘤免疫逃逸在很大程度上仍不清楚。
通过分子检测评估 LSQCC 细胞中 FGFR1、YAP 和 PD-L1 的表达增加或减少。FGFR1 敲低后，在体外与 Jurkat T 细胞共培养后评估癌细胞，并在 C57BL/6 小鼠中分析肿瘤微环境。还探索了 FGFR1 敲低与 PD-1 阻断联合的效果。
在人类 LSQCC 中，FGFR1 的激活与 PD-L1 的转录呈正相关。在 H520 和 HCC95 细胞中，FGFR1 通过 YAP 上调 PD-L1 表达，YAP 通过与其启动子区域结合启动 PD-L1 的转录。FGFR1 敲低可降低肿瘤生长，减少免疫逃逸并诱导 CD8+T 细胞重新激活。FGFR1 敲低与 PD-1 阻断联合具有协同抗肿瘤作用。
FGFR1/YAP/PD-L1 调节轴介导肺鳞状细胞癌中的肿瘤相关免疫抑制，FGFR1 敲低可在肿瘤微环境中重新激活 T 细胞。同时抑制 FGFR1 和 PD-1/PD-L1 通路可能是肺癌患者的一种潜在治疗方法。
