Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.

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 a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are 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, reveals that TFH and tumor-specific exhausted CD8+ T cells are 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 reveals persistence in the peripheral blood for years after ICB therapy. [Display omitted] • Single-cell RNA/TCR-seq with deep intra-patient, regional resolution in NSCLC • TFH, Treg, and CD8+ T cell subsets undergo progressive exhaustion with tumor proximity • LN TCF7 + progenitor exhausted T cells are clonally linked to tumor exhausted T cells • Tumor-specific T cells in aggregate persist after ICB Pai et al. report a single T cell lung cancer dataset allowing for the lineage tracing of T cells across tumor regions, lymph nodes, and peripheral blood. This resource reveals clonal linkage of antigen-specific TCF7 + SELL + progenitor exhausted cells in the lymph node and their exhausted counterparts in the tumor, and long-term peripheral persistence of these cells after checkpoint blockade. [ABSTRACT FROM AUTHOR]