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Targeting GPC3high cancer-associated fibroblasts sensitizing the PD-1 blockage therapy in gastric cancer
1Gastric Surgery Department, The First Affiliated Hospital of Jinzhou Medical University, JinZhou, Liaoning, China.
Abstract:
Cancer-associated fibroblasts (CAFs) are an important part of tumour microenvironment, but its role in immunotherapy of gastric cancer (GC) is still needed to further study. In this study, we firstly distinguish the GC related CAFs via single cell sequencing dataset. CAFs in deep layers of GC tissues gain more developmental potential. Moreover, we found Glypican-3 (GPC3) is up-regulated in the CAFs subgroups of the advanced GC and correlated with poor prognosis in GC patients. In addition, higher GPC3 expression GC patients have higher TIDE (Tumour Immune Dysfunction and Exclusion) score, dysfunction and exclusion score. independent GC cohort also show GC patients with GPC3high CAFs have lower response rate to PD-1 therapy. GPC3 secreted from CAFs up-regulated PD-L1, TIM3, CD24, CYCLIN D1, cMYC and PDK mRNA expression level in HGC-27 cells. At last, in vivo model demonstrate that targeting GPC3high CAFs sensitizing the PD-1 blockage therapy in GC. In conclusion, GPC3 expression in CAFs is a critical prognostic biomarker, and targeting GPC3high cancer-associated fibroblasts sensitizing the PD-1 blockage therapy in GC.Key messagesGlypican-3 (GPC3) is up-regulated in the CAFs subgroups of the advanced gastric cancer.Gastric cancer patients with GPC3high CAFs have lower response rate to PD-1 therapy.Targeting GPC3high CAFs sensitizing the PD-1 blockage therapy in gastric cancer.
Insights
Glypican-3 (GPC3) is elevated in advanced gastric cancer fibroblasts (CAFs) and predicts poor prognosis. Targeting GPC3-high CAFs may improve PD-1 immunotherapy response in gastric cancer patients.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment.
- The specific role of CAFs in gastric cancer (GC) immunotherapy requires further investigation.
Purpose of the Study:
- To identify GC-specific CAFs and investigate the role of Glypican-3 (GPC3) in GC progression and immunotherapy response.
- To evaluate GPC3 as a prognostic biomarker and therapeutic target in GC.
Main Methods:
- Single-cell sequencing to distinguish GC-related CAFs.
- Analysis of GPC3 expression in GC tissues and correlation with prognosis and TIDE scores.
- Assessment of PD-1 therapy response in patients with GPC3-high CAFs.
- In vitro experiments on HGC-27 cells and in vivo models.
Main Results:
- CAFs in deeper GC tissues exhibit enhanced developmental potential.
- GPC3 is upregulated in advanced GC CAFs, correlating with poor prognosis and higher TIDE scores.
- GC patients with GPC3-high CAFs show reduced response to PD-1 therapy.
- GPC3 upregulates PD-L1, TIM3, and other cancer-promoting genes in HGC-27 cells.
- Targeting GPC3-high CAFs sensitizes GC to PD-1 blockade in vivo.
Conclusions:
- GPC3 expression in CAFs serves as a critical prognostic biomarker for gastric cancer.
- Targeting GPC3-high CAFs can enhance the efficacy of PD-1 blockade therapy in gastric cancer.
