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Cbl-b inhibition promotes less differentiated phenotypes of T cells with enhanced cytokine production
•TCR-T cell therapy's effectiveness depends on optimizing cell product quality and quantity.•Pre-activation with Cbl-b-IN-1 boosts TCR expression, cell proliferation, and survival.•Cbl-b-IN-1 maintains T cells' less differentiated states and enhances TCR signaling. For adoptive therapy wit...
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Published in: | Cellular immunology 2024-09, Vol.403-404, p.104863, Article 104863 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | •TCR-T cell therapy's effectiveness depends on optimizing cell product quality and quantity.•Pre-activation with Cbl-b-IN-1 boosts TCR expression, cell proliferation, and survival.•Cbl-b-IN-1 maintains T cells' less differentiated states and enhances TCR signaling.
For adoptive therapy with T cell receptor engineered T (TCR-T) cells, the quantity and quality of the final cell product directly affect their anti-tumor efficacy. The post-transfer efficacy window of TCR-T cells is keen to optimizing attempts during the manufacturing process. Cbl-b is a E3 ubiquitin ligase previously shown with critical negative impact in T cell functions. This study investigated whether strategic inclusion of a commercially available small inhibitor targeting Cbl-b (Cbl-b-IN-1) prior to T cell activation could enhance the quality of the final TCR-T cell product. Examination with both PBMCs and TCR-T cells revealed that Cbl-b-IN-1 treatment promoted TCR expression efficiency, T cell proliferation potential and, specifically, cell survival capability post antigenic stimulation. Cbl-b-IN-1 exposure facilitated T cells in maintaining less differentiated states with enhanced cytokine production. Further, we found that Cbl-b-IN-1 effectively augmented the activation of TCR signaling, shown by increased phosphorylation levels of Zeta-chain-associated protein kinase 70 (ZAP70) and phospholipase c-γ1 (PLCγ1). In conclusion, our results evidence that the inclusion of Cbl-b inhibitor immediately prior to TCR-T cell activation may enhance their proliferation, survival, and function potentials, presenting an applicable optimization strategy for immunotherapy with adoptive cell transfer. |
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ISSN: | 0008-8749 1090-2163 1090-2163 |
DOI: | 10.1016/j.cellimm.2024.104863 |