TGFβ Programs Central Memory Differentiation in Ex Vivo-Stimulated Human T Cells

Area of Science:

• Immunology
• Cell Biology
• Cancer Therapy

Background:

• Adoptive transfer of ex vivo-expanded T cells shows promise for treating malignancies.
• T cells with early memory features are linked to better therapeutic outcomes.
• Optimizing T-cell expansion ex vivo is crucial for enhancing immunotherapy efficacy.

Purpose of the Study:

• To investigate the effect of exogenous transforming growth factor beta (TGFβ) on human T-cell differentiation ex vivo.
• To determine if TGFβ exposure influences the generation of early memory T cells (Tcm).
• To assess the therapeutic potential of TGFβ-conditioned T cells in adoptive immunotherapy.

Main Methods:

• Human T cells were stimulated ex vivo in the presence of exogenous TGFβ.
• Gene expression analysis (BLIMP-1, ID3) and transcriptional profiling were performed.
• T cell functionality, polyfunctionality, and suppressive activity were assessed.
• In vivo studies involved adoptive transfer into immunodeficient mice to evaluate persistence and anti-tumor activity.

Main Results:

• TGFβ exposure led to the accumulation of early/central memory (Tcm) T cells.
• TGFβ suppressed BLIMP-1 and upregulated ID3, inducing an early memory transcriptional signature.
• TGFβ-conditioned T cells exhibited normal expansion, polyfunctionality, and no suppressive activity.
• In vivo, these cells demonstrated enhanced persistence and improved tumor control in chimeric antigen receptor (CAR) T-cell therapy models.

Conclusions:

• Exogenous TGFβ promotes the differentiation of T cells towards an early memory phenotype (Tcm) ex vivo.
• TGFβ signaling can be utilized to enhance the persistence and anti-tumor efficacy of T cells for adoptive immunotherapy.
• This strategy offers a novel approach to program Tcm differentiation for improved cancer treatment outcomes.