Quantifying immune cell telomere content at single-cell resolution in context of PD-1 checkpoint immunotherapy
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Introduction
Biological processes such as aging, carcinogenesis, and immune response rely on the ability to maintain or rapidly expand cell populations. The fitness of the involved cells is constrained by their replicative potential, which is reflected in the cellular telomere content.
Method
We apply TelomereHunter to scATAC-seq data to determine telomere content on single-cell level, in a hematopoietic dataset consisting of 35,139 cells from samples of basal cell carcinoma patients receiving programmed cell death protein 1 (PD1) blockade treatment. Integrating information from open-chromatin-based signatures to assess cell identity, we characterize the heterogeneity of telomere length for individual cell populations pre- and post-immunotherapy.
Results
The extracted telomeric reads reflect the expected telomereome-to-genome fraction. Telomere content distributions differ significantly between cell populations, and the median telomere content in intermediate and terminal exhausted CD8+ T-cells pre-treatment is significantly correlated to response to PD-1 checkpoint blockade. Likewise, telomere content correlates with post-treatment cell proliferation in terminally exhausted and T follicular helper cells from responding patients.
Conclusion
Telomere content measurement from scATAC-seq data has a sufficiently high signal-to-noise ratio to detect significant differences between cell types. Furthermore, the telomere content of CD8+ exhausted T-cells pre-treatment is a putative biomarker for successful PD-1-based immunotherapy.
