FGFR1 promotes tumor immune evasion via YAP-mediated PD-L1 expression upregulation in lung squamous cell carcinoma
Min Lu1, Kaixuan Wang2, Wenxiang Ji2
1Shanghai 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.
Background:
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.
Methods:
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.
Results:
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.
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 pathways may be a possible treatment for lung cancer patients.
Insights
Fibroblast growth factor receptor 1 (FGFR1) activates YAP, which increases PD-L1 expression in lung squamous cell carcinoma (LSQCC), promoting immune evasion. Inhibiting FGFR1 and PD-1 reactivates anti-tumor T cells for synergistic effects.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Fibroblast growth factor receptor 1 (FGFR1) mutations are common in lung squamous cell carcinoma (LSQCC).
- Immune checkpoint inhibitors targeting PD-1 and PD-L1 are effective cancer treatments.
- The role of FGFR1 in regulating tumor immune evasion via downstream molecules like YAP is not well understood.
Purpose of the Study:
- To investigate the regulatory axis of FGFR1, YAP, and PD-L1 in LSQCC.
- To determine if FGFR1 influences tumor immune evasion.
- To explore the therapeutic potential of targeting FGFR1 in combination with PD-1 blockade.
Main Methods:
- LSQCC cells were genetically modified to alter FGFR1, YAP, and PD-L1 expression.
- In vitro co-culture assays with Jurkat T cells were performed.
- Tumor microenvironments in C57BL/6 mice were analyzed.
- The combined effect of FGFR1 knockdown and PD-1 blockade was evaluated.
Main Results:
- FGFR1 activation positively correlated with PD-L1 transcription in human LSQCC.
- FGFR1 upregulated PD-L1 expression via YAP in LSQCC cell lines.
- YAP directly bound to the PD-L1 promoter region, initiating its transcription.
- FGFR1 knockdown reduced tumor growth, decreased immune escape, and reactivated CD8+ T cells.
- Combined FGFR1 knockdown and PD-1 blockade demonstrated synergistic antitumor effects.
Conclusions:
- The FGFR1/YAP/PD-L1 axis mediates immune suppression in LSQCC.
- FGFR1 knockdown can reactivate T cells within the tumor microenvironment.
- Combined inhibition of FGFR1 and PD-1/PD-L1 pathways offers a potential therapeutic strategy for LSQCC patients.
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