Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered...

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Redirecting T cell specificity is crucial for immunotherapy.
• The mechanisms underlying enhanced antitumor function in redirected T cells are not fully understood.
• Understanding the transcriptional basis of T cell receptor (TCR) function is essential for optimizing immunotherapies.

Purpose of the Study:

• To investigate the transcriptional basis of enhanced antitumor function in redirected human CD4+ and CD8+ T cells.
• To characterize the molecular features of T cell receptor 8 (TCR8) expression in T cells.
• To evaluate the potential of TCR8-redirected T cells in a mouse xenograft model.

Main Methods:

• Single-cell RNA sequencing of redirected human CD4+ and CD8+ T cells.
• Bulk and single-cell assays to characterize T cell function.
• Mouse xenograft model to assess in vivo antitumor efficacy.

Main Results:

• TCR8 expression enhanced CD8+ T cell function and preserved less differentiated T cells post-tumor challenge.
• TCR8-expressing CD4+ T cells demonstrated potent antitumor activity.
• Sustained activation of cytotoxicity, costimulation, oxidative phosphorylation, and proliferation genes, with reduced differentiation and exhaustion markers, was observed.

Conclusions:

• TCR8 expression confers enhanced antitumor function to CD4+ T cells through specific transcriptional reprogramming.
• The identified molecular features of TCR8 expression can inform the design of next-generation immunotherapies.
• Redirected T cells hold significant promise for improving cancer treatment strategies.