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Updated: May 17, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy
Ofir Shorer1, Asaf Pinhasi1, Keren Yizhak2
1Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525422, Israel.
Abstract:
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.
Insights
Expanded CD8+ T cell clones reveal distinct transcriptional states linked to patient response to immune checkpoint inhibitors. These findings offer insights into anti-tumor immunity mechanisms and patient outcomes.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- T cell clones are vital for anti-tumor immunity but their role in immune checkpoint inhibitor (ICI) response is not well understood.
- Characterizing T cell clones and their association with clinical outcomes after ICI therapy is crucial for improving treatment strategies.
Purpose of the Study:
- To investigate the role of T cell clone characteristics in predicting response to immune checkpoint inhibitors.
- To identify T cell signatures associated with differential clinical outcomes in cancer patients treated with ICIs.
Main Methods:
- Paired single-cell RNA sequencing and T cell receptor sequencing were performed on 767,606 T cells from 460 samples across six cancer types.
- Analysis included identification of expanded and persistent T cell clones, gene expression profiling, and pseudo-temporal state analysis.
- Comparative analysis of T cell clones in tumor and blood samples from responders versus non-responders.
Main Results:
- A significant signature of response was identified based on expanded CD8+ T cell clones, differentiating responders from non-responders.
- Persistent clones in responders exhibited transcriptional changes indicative of enhanced reinvigoration capacity compared to non-responders.
- De novo clones showed pseudo-temporal state changes associated with clinical outcomes, and shared tumor-blood clones were more abundant in non-responders.
Conclusions:
- Differences in T cell clonal transcriptional states are linked to patient response to immune checkpoint inhibitors.
- Expanded and persistent T cell clones provide valuable biomarkers for predicting ICI efficacy.
- Understanding T cell clonal dynamics offers insights into mechanisms of anti-tumor immunity and potential therapeutic targets.
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