Transcriptomic landscape of peripheral T cells following CAR-T cell therapy in diffuse large B cell lymphoma

CAR-T cell therapy has improved outcomes in relapsed/refractory large B cell lymphoma (LBCL), yet responses remain variable; baseline endogenous T cell state and post-infusion CAR-T differentiation may contribute to this heterogeneity, but the underlying transcriptional programs are incompletely defined.

We performed RNA-sequencing of CD3⁺ T cells from 26 LBCL patients at two time points-pre-apheresis (PA; n = 23) and day 14 post-infusion (D14; n = 9)-and applied differential expression, gene set enrichment analysis (GSEA), and gene regulatory network inference.

In PA T cells, we identified 320 differentially expressed genes enriched for immune-related programs (TCR signaling, T cell differentiation, IL-2-related signaling, TCR regulation of apoptosis and misregulation of cancer) and signatures consistent with immune dysfunction. Unsupervised clustering defined two LBCL T cell expression profiles, which were strongly associated with early disease progression (91% vs 16%; P < 0.001), supporting a hyperactivated yet progressively dysfunctional T cell state that may compromise CAR-T fitness and persistence. At the pathway level, GSEA in LBCL PA T cells showed enrichment of PI3K/AKT/mTOR and MYC target programs together with apoptosis-related signatures.

Transcriptomic heterogeneity in endogenous T cells is strongly linked to early post-CAR-T progression and may inform strategies to optimize CAR-T persistence and efficacy.