FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance

Jing, Weiqiang; Wang, Ganyu; Cui, Zhiwei; Xiong, Gaozhong; Jiang, Xin; Li, Yue; Li, Wushan; Han, Bo; Chen, Shouzhen; Shi, Benkang

doi:10.1158/0008-5472.can-21-2362

Cited by 71 publications

(74 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In studies of BLCA, increasing attention has been paid to infiltrating immune cells (Jing et al, 2022), especially eosinophils. It is well known that eosinophils have been shown to infiltrate multiple tumors and are able to regulate tumor progression either directly by interacting with tumor cells or indirectly by shaping TIME.…”

Section: Discussionmentioning

confidence: 99%

Clinical Eosinophil-Associated Genes can Serve as a Reliable Predictor of Bladder Urothelial Cancer

Song

Peng

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

Background: Numerous studies have shown that infiltrating eosinophils play a key role in the tumor progression of bladder urothelial carcinoma (BLCA). However, the roles of eosinophils and associated hub genes in clinical outcomes and immunotherapy are not well known.Methods: BLCA patient data were extracted from the TCGA database. The tumor immune microenvironment (TIME) was revealed by the CIBERSORT algorithm. Candidate modules and hub genes associated with eosinophils were identified by weighted gene co-expression network analysis (WGCNA). The external GEO database was applied to validate the above results. TIME-related genes with prognostic significance were screened by univariate Cox regression analysis, lasso regression, and multivariate Cox regression analysis. The patient’s risk score (RS) was calculated and divided subjects into high-risk group (HRG) and low-risk group (LRG). The nomogram was developed based on the risk signature. Models were validated via receiver operating characteristic (ROC) curves and calibration curves. Differences between HRG and LRG in clinical features and tumor mutational burden (TMB) were compared. The Immune Phenomenon Score (IPS) was calculated to estimate the immunotherapeutic significance of RS. Half-maximal inhibitory concentrations (IC50s) of chemotherapeutic drugs were predicted by the pRRophetic algorithm.Results: 313 eosinophil-related genes were identified by WGCNA. Subsequently, a risk signature containing 9 eosinophil-related genes (AGXT, B3GALT2, CCDC62, CLEC1B, CLEC2D, CYP19A1, DNM3, SLC5A9, SLC26A8) was finally developed via multiplex analysis and screening. Age (p < 0.001), grade (p < 0.001), and RS (p < 0.001) were independent predictors of survival in BLCA patients. Based on the calibration curve, our risk signature nomogram was confirmed as a good predictor of BLCA patients’ prognosis at 1, 3, and 5 years. The association analysis of RS and immunotherapy indicated that low-risk patients were more credible for novel immune checkpoint inhibitors (ICI) immunotherapy. The chemotherapeutic drug model suggests that RS has an effect on the drug sensitivity of patients.Conclusions: In conclusion, the eosinophil-based RS can be used as a reliable clinical predictor and provide insights into the precise treatment of BLCA.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical Eosinophil-Associated Genes can Serve as a Reliable Predictor of Bladder Urothelial Cancer

Song

Peng

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…Jing, W et al. found that inhibition of FGFR3 in bladder cancer to increase PD-L1 protein levels, leading the inhibition of antitumor activity of CD8+ T cells ( 52 ). These data show the distinct influence on tumor immune environment of different FGFRs , which provide suggestions for prognosis prediction of immunotherapy for GC.…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Song²,

Zhao³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

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.

show abstract

“…FGFR mutations have been associated with a lower PD-L1 expression, decreased T-cell infiltration, and a predominantly luminal-papillary subtype [ 26 , 27 , 28 , 29 ]. In total, 26% of the FGFR GA patients had a PD-L1 CPS ≥ 1 tumoral expression and were associated with a worse outcome.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients

Fernández

Madurga

Moreno

et al. 2022

JCM

View full text Add to dashboard Cite

Fibroblast growth factor receptor (FGFR) genomic alterations (GAs) represent an actionable target, key to the pathogenesis of some urothelial cancers (UCs). Though FGFR GAs are common in noninvasive UC, little is known about their role in the metastatic(m) setting and response to therapy. This study aimed to assess the impact of FGFR alterations on sensitivity to systemic treatments and survival and to validate Bajorin’s and Bellmunt’s prognostic scores in mUC patients according to their FGFR status. We retrospectively analyzed data from 98 patients with tumor-sequenced UC who received treatment between January 2010 and December 2020. Up to 77 developed metastatic disease and were deemed the study population. Twenty-six showed FGFR GAs. A trend toward a better response to cisplatin and checkpoint inhibitors was suggested favoring FGFR GA tumors. FGFR GA patients who received an FGFR inhibitor as first-line had poorer responses compared with other options (20% vs. 68.4%, p = 0.0065). Median PFS was 6 vs. 5 months in the FGFR GA vs. FGFR WT cohort (p = 0.71). Median OS was significantly worse in the FGFR GA vs. FGFR WT cohort (16.2 vs. 31.9 months, p = 0.045). Multivariate analyses deemed FGFR GAs as a factor independently associated with the outcome (HR 2.59 (95% CI 1.21–5.55)). Bajorin’s model correctly predicted clinical outcomes in the whole study population but not in FGFR GA cases. FGFR GAs are a relevant biomarker in mUC that could condition the response to systemic therapy. New prognostic models, including this molecular determination, should be designed and validated.

show abstract

FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance

Cited by 71 publications

References 47 publications

Clinical Eosinophil-Associated Genes can Serve as a Reliable Predictor of Bladder Urothelial Cancer

Clinical Eosinophil-Associated Genes can Serve as a Reliable Predictor of Bladder Urothelial Cancer

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

Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients

Contact Info

Product

Resources

About