Journal
CELLULAR IMMUNOLOGY
Volume 379, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.cellimm.2022.104577
Keywords
FGFR1; PD-L1; Driver mutation; Tumor immune evasion; Combination therapy
Categories
Funding
- National Key R&D Program of China [2016YFC1303300]
- National Natural Science Foundation of China [81672272]
- Science and Technology Innovation program of Shanghai [19411950500]
- Shanghai Municipal Sci-ence and Technology Commission Research Project [17431906103]
- Program for Outstanding Medical Academic Leader [19YF1407200]
- Shanghai Sailing Program [19YF1407300]
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FGFR1 activation is positively correlated with PD-L1 transcription in lung squamous cell carcinoma. FGFR1 upregulates PD-L1 expression through YAP, while FGFR1 knockdown decreases tumor growth, reduces immune escape, and induces reactivation of CD8+ T cells. The combination of FGFR1 knockdown and PD-1 blockade synergistically exerts antitumor effects.
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.
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