Targeting GPC3 ^high cancer-associated fibroblasts sensitizing the PD-1 blockage therapy in gastric cancer

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 GPC3 high 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 GPC3 high CAFs sensitizing the PD-1 blockage therapy in GC. In conclusion, GPC3 expression in CAFs is a critical prognostic biomarker, and targeting GPC3 high cancer-associated fibroblasts sensitizing the PD-1 blockage therapy in GC. Key messages Glypican-3 (GPC3) is up-regulated in the CAFs subgroups of the advanced gastric cancer. Gastric cancer patients with GPC3 high CAFs have lower response rate to PD-1 therapy. Targeting GPC3 high CAFs sensitizing the PD-1 blockage therapy in gastric cancer.

Mapping knowledge structure and themes trends of cancer-associated fibroblasts: a text-mining study

“…This alteration hinders the movement of T cells, particularly CD8 + T cells, creating a barrier effect against the infiltration of drugs and immune cells and ultimately leading to the suppression of anti-tumor immunity ( García-Palmero et al, 2016 ; Zhang et al, 2016 ). In light of the immunosuppressive effects employed by CAFs in resistance to PD-1/PD-L1 immunotherapy, therapeutic interventions targeting key molecules within the underlying mechanism such as TGF-β, NOX4 and exosome, are being explored in clinical trials to augment tumor immune efficacy against PD-1/PD-L1 ( Pan et al, 2020 ; Kato et al, 2021 ; Li et al, 2023 ). Nonetheless, recent investigations indicated the presence of distinct CAFs subpopulations including tumor-suppressing and tumor-promoting phenotypes with differing molecular profiles and functions ( Öhlund et al, 2017 ).…”

Single-cell data revealed CD14-type and FCGR3A-type macrophages and relevant prognostic factors for predicting immunotherapy and prognosis in stomach adenocarcinoma

“…For the cell clusters that were clustered and obtained, cellular annotation analysis was conducted by marker genes in order to investigate the cell types of these cell clusters. Marker genes were derived from biomarkers found in PD-L1 blockade therapy in gastric cancer by Li et al (2023) and from the SingleCellBase database ( ) ( Meng et al, 2023 ). The type of cell cluster was determined based on marker genes expression.…”

Clinical application of LC-MS/MS to detect fat-soluble vitamins in gastric cancer

“…In recent years, with the development of medical technology, the diagnosis rate, survival time and quality of life of early gastric cancer have been signi cantly improved. However, 2/3 of the patients are found in advanced stages, and even with chemotherapy, radiotherapy or immunotherapy based on surgery, the ve-year survival rate is still less than 30% [2].…”