Single-cell insights into CD8 T cell differentiation and exhaustion in the tumor microenvironment 3220

Abstract Description Tumors attract both tumor-specific T cells and bystander T cells that do not directly fight the tumor. Understanding T-cell heterogeneity is essential for improving the efficacy of immunotherapies. Here, we demonstrate that most neoantigen-specific CD8+ T cells in the tumor are double-positive for PD-1 and IFN-γ, while those in the lymph nodes exhibit heterogeneous expression of PD-1 and IFN-γ. Using single-cell RNA sequencing (scRNA-seq), we show that the tissue microenvironment profoundly influences the transcriptional profiles of tumor-reactive T cells. In tumors, PD-1 marks highly clonally expanded tumor-reactive T cells. In contrast, neoantigen-specific CD8+ T cells in the lymph nodes include a TCF7+ stem-like subset and a transitional subset progressing toward terminal exhaustion. This study provides critical insights into the dynamic differentiation of tumor-specific T cells and highlights potential therapeutic targets for enhancing anti-tumor immunity. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)