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

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Chimeric antigen receptor (CAR)-T cell therapy shows promise for relapsed/refractory large B cell lymphoma (LBCL).
• Patient responses to CAR-T therapy are variable.
• Endogenous T cell state and CAR-T cell differentiation influence treatment heterogeneity, but underlying transcriptional programs are not fully understood.

Purpose of the Study:

• To investigate the transcriptional landscape of endogenous T cells in LBCL patients.
• To identify T cell profiles associated with CAR-T therapy outcomes.
• To explore the relationship between baseline T cell state and CAR-T cell persistence.

Main Methods:

• RNA sequencing of CD3+ T cells from LBCL patients pre-apheresis and post-infusion.
• Differential gene expression analysis.
• Gene set enrichment analysis (GSEA) and gene regulatory network inference.

Main Results:

• Identified differentially expressed genes in pre-apheresis T cells related to immune dysfunction, including TCR signaling and apoptosis.
• Defined two distinct LBCL T cell expression profiles associated with early disease progression (91% vs. 16%).
• GSEA revealed enrichment of PI3K/AKT/mTOR, MYC targets, and apoptosis signatures in LBCL T cells.

Conclusions:

• Transcriptomic heterogeneity in endogenous T cells correlates with early progression after CAR-T therapy.
• Baseline T cell state may impact CAR-T cell fitness and persistence.
• Findings suggest potential strategies to enhance CAR-T therapy efficacy in LBCL.