Single-cell transcriptomic analysis reveals CD8 + T cell heterogeneity and identifies a prognostic signature in cervical cancer.

Abstract

Background: In recent years, immunotherapy has made significant progress. However, the understanding of the heterogeneity and function of T cells, particularly CD8 + T cells, in cervical cancer (CESC) microenvironment remains insufficient. We aim to characterize the heterogeneity, developmental trajectory, regulatory network, and intercellular communication of CD8 + T cells in cervical squamous cell carcinoma and to construct a prognostic risk model based on the transcriptomic characteristics of CD8 + T cells.

Methods: We integrated single-cell RNA sequencing data from CESC tumor samples with bulk transcriptome data from TCGA and GEO databases. We identified CD8 + T cell subsets in the CESC microenvironment, revealing significant interactions between CD8 + T cells and other cell types through intercellular communication analysis. Pseudotime trajectory analysis revealed dynamic transcriptional regulation during CD8 + T cell differentiation and functional acquisition processes. We constructed a transcriptional regulatory network for CESC CD8 + T cells, identifying key transcription factors. Based on CD8 + T cell-related genes, a prognostic risk model comprising eight core genes was developed and validated using machine learning.

Results: We identified four distinct CD8 + T cell subsets, namely progenitor, intermediate, proliferative, and terminally differentiated, each exhibiting unique transcriptomic characteristics and functional properties. CD8 + T cell subsets interact with macrophages through different ligand-receptor networks, including the CCL-CCR signaling pathway and costimulatory molecules. Sorafenib was identified as a potential immunotherapeutic drug through drug screening. Experimental validation demonstrated that sorafenib enhances the cytotoxicity of CD8 + T cells by increasing the secretion of IFN-γ and TNF-α, thereby significantly inhibiting the invasiveness and survival of CESC cells.

Conclusions: Our study provides valuable insights into the heterogeneity and functional diversity of CD8 + T cells in CESC. We demonstrate that a CD8 + T cell-related prognostic signature may serve as a potential tool for risk stratification in patients with CESC. Additionally, our finding suggests that sorafenib could be a promising therapeutic candidate for improving antitumor immunity in this patient population.