T cell receptor-centric perspective to multimodal single-cell data analysis

The T cell receptors (TCR) carry critical information regarding T cell functionality. Yet is often overlooked in single cell experiments, which commonly focus on gene expression (GEx)-first analysis. Here we propose a dedicated TCR-first analysis for single T cell data, implemented as the STEGO.R package. A curated T cell atlas was built using STEGO.R from 12 prominent human studies, containing in total 500,000 T cells spanning multiple diseases, including melanoma, head-and-neck cancer, T-cell cancer, and lung transplantation, allowing the reanalysis of these datasets. The TCR-first approach was able to highlight dynamic features in hyperexpanded clones and treatment-specific changes, which were missed in the original GEx-first analyses. This meta-analysis also revealed previously unknown public T-cell clusters with common gene signatures and antigen specificities. Overall, adopting the TCR-first approach revealed T-cell features often missed by conventional GEx-focused methods and the STEGO.R tool facilitates this paradigm shift. ### Competing Interest Statement BO, KL and PM hold shares in ImmuneWatch BV, an immunoinformatics company, which developed IMW DETECT.