GSE185204
Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scRNA-seq]
Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from 3 patients with lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells were enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, revealed that TFH and tumor-specific exhausted CD8+ T cells could be clonally linked to TCF7+ SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones revealed persistence in the peripheral blood for years after ICB therapy. Overall design: CD3+ T cells were sorted from tumor, adjacent normal, and lymph node regions of patients with lung cancer treated with anti-PD-1 therapy, and subjected to paired single-cell RNA- and TCR-sequencing on the 10x Genomics platform.