Integrated single-cell and bulk RNA sequencing analyses identify an immunotherapy nonresponse-related fibroblast signature in gastric cancer

Qian Peng ¹, Peiling Zhang , Guolong Liu

⁰Department of Medical Oncology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.

Anti-Cancer Drugs +

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August 7, 2024

View abstract on PubMed

Summary

This study identifies a fibroblast-associated gene signature that predicts nonresponse to immune checkpoint inhibitors (ICI) in gastric cancer. This signature may help overcome immune resistance and guide treatment strategies.

Area Of Science

Oncology
Immunology
Bioinformatics

Background

Nonresponse to immune checkpoint inhibitors (ICI) in gastric cancer (GC) remains a significant clinical challenge.
Cancer-associated fibroblasts (CAFs) exhibit protumor activities, suggesting their potential as therapeutic targets, yet a CAF-related signature for predicting immunotherapy response in GC is lacking.

Purpose Of The Study

To identify activated fibroblast genes (AFGs) associated with prognosis and immunotherapy nonresponse in gastric cancer.
To construct a prognostic signature based on identified AFGs to predict clinical outcomes and immunotherapy response in GC patients.

Main Methods

Utilized single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) data from GC immunotherapy cohorts.
Performed cellular infiltration, receptor-ligand interaction, and evolutionary trajectory analyses.
Employed Weighted Gene Correlation Network Analysis (WGCNA) and Cox/LASSO regression to construct a prognostic model using AFGs and key module genes.

Main Results

Identified 20 AFGs associated with poor prognosis and tumor progression in GC.
Developed a three-gene signature (FRZB, SPARC, FKBP10) that independently predicts clinical outcomes and immunotherapy nonresponse.
The high-risk group exhibited increased infiltration of CD4 memory T cells, resting mast cells, and M2 macrophages, indicating tumor immune exclusion and reduced immunotherapy sensitivity.

Conclusions

A novel fibroblast-associated gene signature accurately predicts immune checkpoint inhibitor nonresponse in gastric cancer.
This signature serves as an independent prognostic factor and highlights potential strategies to overcome immune resistance in GC.
Patients with high-risk scores may benefit from alternative therapies, such as small molecule agents.