scXpand: Pan-cancer detection of T cell clonal expansion from single-cell RNA sequencing without paired single-cell TCR sequencing.

Advances in single-cell sequencing have enabled detailed characterization of T cell clonal dynamics in cancer. However, analyses aiming to link the transcriptional landscape to T cell clonality remain limited by confounding factors unequally controlled in different studies. To address this challenge, we developed scXpand, a machine-learning framework for pan-cancer detection of T cell clonal expansion directly from single-cell RNA sequencing (scRNA-seq), without paired T cell receptor (TCR) sequencing. Trained and tested using our in-house-constructed human pan-cancer database of paired scRNA/TCR-seq profiles from 2.6 million T cells, scXpand demonstrates robust and accurate detection of clonal expansion across tissues and T cell subtypes. Applied to datasets lacking TCR sequencing, scXpand predictions correspond with known characteristics of the tumor microenvironment. Overall, scXpand provides a framework for detecting T cell clonal expansion across cancers directly from scRNA-seq, enabling broad use on datasets lacking scTCR-seq, while supporting scalable, memory-efficient processing, including pre-trained models with user-friendly documentation for flexible applications.