Identifying Distinct Molecular Response of CAR-T cells to Solid Tumors by Synthetic Single-Cell Transcriptomic Analyses

Chimeric Antigen Receptor (CAR)-T cell therapy is a novel personalized treatment that engineers patient immune cells to fight against cancer cells. Recently, CAR-T cell therapy has demonstrated remarkable success in the treatment of hematopoietic cancers, whereas the treatment of solid tumors is more challenging, likely in part due to their severely immunosuppressive tumor microenvironment. To address distinct molecular responses of CAR-T cells between blood and solid tumors, we performed synthetic analysis of single-cell transcriptomics of CAR-T cells and identified unique immunosuppressive subpopulations and aberrant signalling inductions in CD4 ⁺ and CD8 ⁺ CAR-T cells in the context of solid tumors. Furthermore, we also found that PD-1-independent exhaustion-like CD8 ⁺ CAR-T cells, characterized by high expression of TNFRSF9 and CCL3 , were preferentially generated under solid tumor stimulation. Collectively, our comprehensive analyses provide essential molecular insights into solid tumor-stimulated CAR-T cells and assists in overcoming the limited efficacy of CAR-T cell therapy against solid tumors.