Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies

Adachi, Yusuke; Kono, Hiroshi; Ichikawa, Kenji; Fukushima, Sayo; Ozawa, Yoichi; Yamaguchi, Shogo; Goda, Satoshi; Kimura, Takayuki; Kodama, Kotaro; Matsuki, Masahiro; Miyano, Saori Watanabe; Yokoi, Akira; Kato, Yu; Funahashi, Yasuhiro

doi:10.1158/0008-5472.can-20-2426

Cited by 92 publications

(82 citation statements)

References 56 publications

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“…Further research results showed that epi-PCGs had more transcripts and exons than non-epi-PCGs, but the transcript length was relatively short, indicating that although epi-PCGs accounted for a relatively small proportion, it is possible that the level of transcription protein was decreased. These epi-PCG-related pathways include “bladder cancer”, “hematopoietic cell lineage” ( 49 – 51 ), and “JAK-STAT signaling pathway” ( 52 – 54 ), which are related to tumor progression, indicating that these epi-PCGs play a pivotal role in the occurrence and development of tumors.…”

Section: Discussionmentioning

confidence: 99%

Identification of epigenetic dysregulation gene markers and immune landscape in kidney renal clear cell carcinoma by comprehensive genomic analysis

Xie

Wu²,

He³

et al. 2022

Front. Immunol.

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Kidney cancer is one the most lethal cancers of the urinary system, but current treatments are limited and its prognosis is poor. This study focused on kidney renal clear cell carcinoma (KIRC) and analyzed the relationship between epigenetic alterations and KIRC prognosis, and explored the prognostic significance of these findings in KIRC patients. Based on multi-omics data, differentially expressed histone-modified genes were identified using the R package limma package. Gene enhancers were detected from data in the FANTOM5 database. Gene promoters were screened using the R package ChIPseeker, and the Bumphunter in the R package CHAMP was applied to screen differentially methylated regions (DMR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis of genes was performed using the R package clusterProfiler. We identified 51 dysregulated epigenetic protein coding genes (epi-PCGs) from 872 epi-PCGs, and categorized three molecular subtypes (C1, C2, and C3) of KIRC samples with significantly different prognosis. Notably, among the three molecular subtypes, we found a markedly differential immune features in immune checkpoints, cytokines, immune signatures, and immune cell distribution. C2 subtype had significantly lower enrichment score of IFNγ, cytotoxic score (CYT), and angiogenesis. In addition, an 8-gene signature containing 8 epi-PCGs (ETV4, SH2B3, FATE1, GRK5, MALL, HRH2, SEMA3G, and SLC10A6) was developed for predicting KIRC prognosis. Prognosis of patients with a high 8-gene signature score was significantly worse than those with a low 8-gene signature score, which was also validated by the independent validation data. The 8-gene signature had a better performance compared with previous signatures of KIRC. Overall, this study highlighted the important role of epigenetic regulation in KIRC development, and explored prognostic epi-PCGs, which may provide a guidance for exploiting further pathological mechanisms of KIRC and for developing novel drug targets.

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Section: Discussionmentioning

confidence: 99%

Identification of epigenetic dysregulation gene markers and immune landscape in kidney renal clear cell carcinoma by comprehensive genomic analysis

Xie

Wu²,

He³

et al. 2022

Front. Immunol.

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“…After preprocessing, 80 and 63 UM samples remained in TCGA and GSE22138 cohorts, respectively ( Tables S1, S2 ). Limma R package ( 18 , 19 ) was used to normalize the quantile of gene expression data.…”

Section: Methodsmentioning

confidence: 99%

Integration of Bulk RNA Sequencing and Single-Cell RNA Sequencing to Reveal Uveal Melanoma Tumor Heterogeneity and Cells Related to Survival

et al. 2022

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Molecular classification based on transcriptional characteristics is often used to study tumor heterogeneity. Human cancer has different cell populations with distinct transcription in tumors, and their heterogeneity is the focus of tumor therapy. Our purpose was to explore the tumor heterogeneity of uveal melanoma (UM) through RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq). Based on the consensus clustering assays of the prognosis-related immune gene set, the immune subtype (IS) of UM and its corresponding immune characteristics were comprehensively analyzed. The heterogeneous cell groups and corresponding marker genes of UM were identified from GSE138433 using scRNA-seq analysis. Pseudotime trajectory analysis and SCENIC analysis were conducted to explore the trajectory of cell differentiation and the regulatory network of single-cell transcription factors (TFs). Based on 37 immune gene sets, UM was divided into two different immune subtypes (IS1 and IS2). The two kinds of ISs have different characteristics in prognosis, immune-related molecules, immune score, and immune cell infiltration. According to 11,988 cells of scRNA-seq data from six UM samples, 11 cell clusters and 10 cell types were identified. The subsets of C1, C4, C5, C8, and C9 were related to the prognosis of UM, and different TF–target gene regulatory networks were involved. These five cell subsets differentiated into 3 different states. Our results provided valuable information about the heterogeneity of UM tumors and the expression patterns of TFs in different cell types.

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“…Thus, it is critical to identify more effective immunotherapy targets and predictive biomarkers. Previous experiments have found that FGFR is associated with immunity ( 17 , 18 ), but the correlation between FGFR protein expression and tumor-infiltrating immune cells is not clear. In addition, the underlying mechanism how FGFRs regulates the immune environment and their association with the efficiency of immunotherapy remains unclear.…”

Section: Introductionmentioning

confidence: 94%

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

Yang

Song²,

Zhao³

et al. 2022

Front. Oncol.

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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.

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Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies

Cited by 92 publications

References 56 publications

Identification of epigenetic dysregulation gene markers and immune landscape in kidney renal clear cell carcinoma by comprehensive genomic analysis

Identification of epigenetic dysregulation gene markers and immune landscape in kidney renal clear cell carcinoma by comprehensive genomic analysis

Integration of Bulk RNA Sequencing and Single-Cell RNA Sequencing to Reveal Uveal Melanoma Tumor Heterogeneity and Cells Related to Survival

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

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