Available online 9 July 2022, 104577
Highlights•FGFR1 and PD-L1 co-expressed in human lung cancer samples from public database.
•FGFR1 activated PD-L1 via YAP in human squamous cell carcinoma.
•Knockdown of FGFR1 partially reversed tumor immune evasion both in vitro and in vivo.
•The combination of FGFR1 knockdown and PD-1 blockade synergistically exerted antitumor effects.
AbstractBackgroundVariations 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.
MethodsLSQCC 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.
ResultsIn 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 and reduced immune escape and reactivation of CD8+ T cells. The combination of FGFR1 knockdown and PD-1 blockade synergistically exerted antitumor effects.
ConclusionsThe 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.
KeywordsFGFR1
PD-L1
driver mutation
tumor immune evasion
combination therapy
AbbreviationsFGFR1fibroblast growth factor receptor 1
LSQCClung squamous cell carcinoma
PD-L1programmed death ligand-1
YAPYes-associated protein
FGF2fibroblast growth factor 2
TCGAThe Cancer Genome Atlas
TMEtumor microenvironment
TEADtranscriptional enhanced associate domain
siRNAsshort interfering RNAs
LAG-3lymphocyte activation gene-3
TNF-αtumor necrosis factor-alpha
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