Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy.

Despite the crucial role of T cell clones in anti-tumor activity, their characterization and association with clinical outcomes following immune checkpoint inhibitors are lacking. Here, we analyzed paired single-cell RNA sequencing/T cell receptor sequencing of 767,606 T cells across 460 samples spanning 6 cancer types. We found a robust signature of response based on expanded CD8⁺ clones that differentiates responders from non-responders. Analysis of persistent clones showed transcriptional changes that are differentially induced by therapy in the different response groups, suggesting an improved reinvigoration capacity in responding patients. Moreover, a gene trajectory analysis revealed changes in the pseudo-temporal state of de novo clones that are associated with clinical outcomes. Lastly, we found that clones shared between tumor and blood are more abundant in non-responders and execute distinct transcriptional programs. Overall, our results highlight differences in clonal transcriptional states that are linked to patient response, offering valuable insights into the mechanisms driving effective anti-tumor immunity.