FGFR1 Promotes Tumor Immune Evasion via YAP-Mediated PD-L1 Expression Upregulation in Lung Squamous Cell Carcinoma

Abstract

Background: Variations in fibroblast growth factor receptor 1 (FGFR1), which occur frequently, are common driver mutations of lung squamous cell carcinoma. Immune checkpoint inhibitors targeting programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are powerful anticancer weapons. Activation of FGFR1 leads to tumorigenesis through multiple downstream molecules, including Yes-associated protein (YAP), but whether and how FGFR1 regulates tumor immune evasion remain largely unclear.

Methods: H520 and HCC95 cells were treated with siRNA and plasmids to increase or decrease the expression of FGFR1, YAP and PD-L1, as assessed by molecular assays of protein and mRNA expression. The interaction between YAP and PD-L1 was verified by chromatin immunoprecipitation. After FGFR1 knockdown by shRNA, cancer cells were cocultured with Jurkat T cells, and then cell proliferation and activity were assessed. In C57BL/6 mice, the tumor immune microenvironment was analyzed by flow cytometry, immunofluorescence and immunohistochemistry after FGFR1 knockdown. The effect of the combination of FGFR1 knockdown and PD-1 blockade was explored both in vitro and in vivo.

Results: 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. Both in vitro and in vivo, FGFR1 knockdown decreased tumor growth and reduced immune escape and reactivation of T cells. The combination of FGFR1 knockdown and PD-1 blockade synergistically exerted antitumor effects. In human LSQCC, the expression of fibroblast growth factor 2 (FGF2), the activator of FGFR1, was positively correlated with that of PD-L1 at the mRNA level.

Conclusions: 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 may be a possible treatment for lung cancer patients.

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