Single‑Cell Profiling Reveals Developmental Trajectories and identifies SYK and TIM3 as Targets in some T Cell Lymphomas

T cell lymphomas (TCL) are a heterogeneous collection of malignancies whose origins and pathogenesis are poorly understood and for which few efficacious therapeutic options exist. Here, we conduct single-cell transcriptomic profiling spanning eight TCL entities and describe entity-associated programmes. We predict the cell of origin for these tumours through an integrative analysis of transcriptome and T cell receptor (TCR) maturation states. By identifying tumours with TCR states ranging from the pre-TCR through non-productive and productive TCR alpha and beta chain rearrangements we shed new light on their developmental origins. Furthermore, we apply our drug2cell computational drug target predictions with drug screens using patient-derived cell models, systematically benchmarking the performance of drug2cell and validating compounds and targets. This process identifies SYK inhibitors as a therapeutic opportunity and prioritises TIM3 for immunotherapy based on combined spatial transcriptomics analysis. Overall, our data provide a resource for diagnostics and therapies for tumours of critical unmet need.