High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells

Russell W Cochrane; Rob A. Robino; Bryan Granger; Eva Allen; Silvia G. Vaena; Martin J. Romeo; Aguirre A. de Cubas; Stefano Berto; Leonardo M. R. Ferreira

doi:10.1016/j.omtm.2024.101385

November 18, 2024Molecular Therapy — Methods & Clinical DevelopmentOpen Access

High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells

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Key Points

Determine how chimeric antigen receptor (CAR) affinity affects the stability, gene expression, and phenotypic program of human regulatory T cells.
Engineered human regulatory T cells (Tregs) with chimeric antigen receptors possessing varying levels of antigen affinity.
Evaluated post-activation cell-surface marker expression, effector T cell gene expression profiles, and inflammatory cytokine secretion.
High-affinity CAR activation prompted human regulatory T cells to aberrantly express CD40L on their surface and secrete IFN-γ.
Decreasing CAR antigen affinity significantly reduced effector T cell gene signatures and diminished inflammatory cytokine output.

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Implication

Experimental study reveals high-affinity CAR signaling drives an inflammatory switch in human regulatory T cells, suggesting tailored receptor affinity improves therapeutic stability.

Abstract

CAR Tregs uniquely acquiring CD40L surface expression and producing IFN-γ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy.

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Cite This Study

Cochrane et al. (2024) studied this question.

synapsesocial.com/papers/6a11e4c75a604c357c21c281 https://doi.org/10.1016/j.omtm.2024.101385

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High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells

Key Points

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Implication

Abstract

Discussion

Cite This Study

High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells

Key Points

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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