Comprehensive analysis of the prognostic value and immune infiltration of FGFR family members in gastric cancer

Abstract

BackgroundFibroblast growth factor receptors (FGFRs) modulate numerous cellular processes in tumor cells and tumor microenvironment. However, the effect of FGFRs on tumor prognosis and tumor-infiltrating lymphocytes in gastric cancer (GC) remains controversial.MethodsThe expression of four different types of FGFRs was analyzed via GEPIA, TCGA-STAD, and GTEX databases and our 27 pairs of GC tumor samples and the adjacent normal tissue. Furthermore, the Kaplan–Meier plot and the TCGA database were utilized to assess the association of FGFRs with clinical prognosis. The R software was used to evaluate FGFRs co-expression genes with GO/KEGG Pathway Enrichment Analysis. In vitro and in vivo functional analyses and immunoblotting were performed to verify FGFR4 overexpression consequence. Moreover, the correlation between FGFRs and cancer immune infiltrates was analyzed by TIMER and TCGA databases. And the efficacy of anti-PD-1 mAb treatment was examined in NOG mouse models with overexpressed FGFR1 or FGFR4.ResultsThe expression of FGFRs was considerably elevated in STAD than in the normal gastric tissues and was significantly correlated with poor OS and PFS. ROC curve showed the accuracy of the FGFRs in tumor diagnosis, among which FGFR4 had the highest ROC value. Besides, univariate and multivariate analysis revealed that FGFR4 was an independent prognostic factor for GC patients. According to a GO/KEGG analysis, the FGFRs were implicated in the ERK/MAPK, PI3K-AKT and extracellular matrix (ECM) receptor signaling pathways. In vivo and in vitro studies revealed that overexpression of FGFR4 stimulated GC cell proliferation, invasion, and migration. In addition, FGFR1 expression was positively correlated with infiltrating levels of CD8+ T-cells, CD4+ T-cells, macrophages, and dendritic cells in STAD. In contrast, FGFR4 expression was negatively correlated with tumor-infiltrating lymphocytes. Interestingly, overexpression of FGFR1 in the NOG mouse model improved the immunotherapeutic impact of GC, while overexpression of FGFR4 impaired the effect. When combined with an FGFR4 inhibitor, the anti-tumor effect of anti-PD-1 treatment increased significantly in a GC xenograft mouse model with overexpressed FGFR4.ConclusionsFGFRs has critical function in GC and associated with immune cell infiltration, which might be a potential prognosis biomarker and predictor of response to immunotherapy in GC.

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers

“…Immunotherapy such as anti-PDL1 therapy has been shown to have more effect in FGFR wild-type tumors in bladder cancer cell lines while less effects from immunotherapy were observed in FGFR4-overexpressed gastric cancer cells [144,145]. Patients with FGFR1overexpressed melanoma were also found to have less response to pembrolizumab while FGFR-altered HCC tends to have progressive disease after immunotherapy [146][147][148].…”

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

“…This is associated not only with T-cell exhaustion due to increased PD-1 expression, but also with decreased clonality and infiltration. FGFR4 expression is negatively correlated with the number of infiltrating lymphocytes in gastric malignancies [ 54 ]. FGFR3 -mutant urothelial carcinomas have also been noted to possess an immune microenvironment background with increased T-cell exhaustion [ 55 ].…”

“…This FGFR signaling promotes interleukin (IL)-2 production by degrading IκBα and activating NF-κB, which promotes T-lymphocyte proliferation by activating RAS and PI3K with the help of SNT-like proteins [ 71 , 72 ]. Bioinformatic analysis of tissues from gastric cancer patients also revealed that the degree of infiltration of CD8 + and CD4 + T-cells, macrophages and DCs was positively correlated with the expression of FGFR1 in tumor cells [ 54 ]. This suggests that the mechanisms by which different FGFR activating alterations act in tumors may be different and regulated by different factors and require more detailed and comprehensive studies for elucidation.…”

“…As mentioned previously, oncogenic FGFR mutations are closely associated with a non-inflammatory environment in certain malignancies, which may lead to poor responses to ICB treatment [ 9 ]. It has been demonstrated that overexpression of FGFR4 impairs the immunotherapeutic effect in gastric malignancies [ 54 ]. Consistently, a mathematical model of bladder cancer has shown that FGFR WT tumors are more susceptible to anti-PD-L1 therapy than FGFR -mutated tumors [ 183 ].…”

“…Paradoxically, murine models of gastric cancer point to an improved immunotherapeutic effect of FGFR1 expression [ 54 ]. Analysis of clinical data noted that melanoma patients with FGFR mutations treated with ICI had better survival than those without mutations (median OS: 60.00 months vs. 31.00 months; HR: 0.58, 95% CI: 0.42–0.80; P = 0.0051) [ 193 ].…”