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| Home > Publications database > Tempered signal strength via low-dose MEK inhibition optimizes therapeutic performance of engineered T cells. |
| Home > Publications database > Tempered signal strength via low-dose MEK inhibition optimizes therapeutic performance of engineered T cells. |
| Journal Article | DKFZ-2025-02692 |
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2025
BioMed Central
London
Abstract: Optimizing T cell activation strength is emerging as a critical factor in improving adoptive cellular therapy (ACT). We previously reported that neoantigen-specific T cell receptor (TCR) clonotypes from a patient with metastatic melanoma exhibited enhanced resilience to repeated stimulation when initially activated at moderate levels.Building on these observations, we applied transient, low-dose MEK inhibition (MEKi) to fine-tune T cell signal strength during early activation. We evaluated this combinatorial strategy in vitro using co-cultures of CD8+ T cells engineered with patient-derived neoantigen-specific TCRs, alongside chimeric antigen receptor-T cells, bispecific T cell engagers, and non-engineered tumor-infiltrating lymphocytes (TILs). In vivo efficacy was evaluated in a xenograft model with intravenous TCR-T cell transfer and systemic low-dose MEKi.MEKi co-treatment induced a more tempered activation profile that enhanced T cell proliferation, fitness, and persistence under strong stimulation. These effects were consistent across various in vitro and in vivo models for engineered T cells as well as primary melanoma-derived TILs. MEKi dampened the pro-inflammatory T cell activation profile, most notably diminishing tumor necrosis factor (TNF) secretion, mechanistically driven by coordinated and selective disruption of the key transcriptional regulators nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and nuclear factor of activated T cells (NFAT) while partly preserving activator protein 1 (AP-1) activity.These findings highlight moderate activation as a critical determinant of engineered T cell long-term performance. Low-dose MEKi offers a therapeutic tool for fine-tuning T cell activation and enhancing ACT efficacy.
Keyword(s): Humans (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Melanoma: immunology (MeSH) ; Melanoma: therapy (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Lymphocyte Activation: drug effects (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; Protein Kinase Inhibitors: therapeutic use (MeSH) ; Female (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes (MeSH) ; T cell receptor - TCR ; adoptive cell therapy - ACT ; combination therapy ; immunotherapy ; Protein Kinase Inhibitors
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