p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells
7 affiliations
- 1Department of Surgery, UCLA
- 2Division of Surgical Oncology, UCLA
- 3Division of Hematology/Oncology, UCLA
- 4Department of Pediatrics, UCLA
- 5David Geffen School of Medicine, UCLA
- 6UCLA Bioengineering, UCLA
- 7Jonsson Comprehensive Cancer Center, Sarcoma Oncology Program, UCLA
Abstract
Adoptive T-cell therapies using chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) have transformed cancer treatment but remain limited by poor persistence and progressive T-cell exhaustion. Manufacturing strategies that promote memory T-cell formation may improve therapeutic durability. Here we investigated whether transient pharmacologic activation of the p53 pathway influences the differentiation and function of human CD8+ T cells. p53 expression was minimal in quiescent naïve CD8+ T cells but was rapidly induced following T-cell receptor activation. Pharmacologic inhibition of the p53 negative regulator MDM2 increased p53 protein levels and promoted expansion of central memory and stem-like memory T-cell subsets during clonal proliferation. Treated cells displayed enhanced mitochondrial fitness, increased polyfunctional cytokine production, and transcriptional programs consistent with memory differentiation and reduced exhaustion. Importantly, TCR-engineered CD8+ T cells generated in the presence of the MDM2 inhibitor Navtemadlin demonstrated superior tumor-cell killing in vitro compared with conventionally manufactured cells. These findings identify transient p53 activation as a pharmacologic strategy to enhance memory programming during T-cell manufacturing and suggest a clinically feasible approach to improve the efficacy of adoptive T-cell immunotherapies.
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BibTeX
@article{jesus2026activation,
title = {{p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells}},
author = {Alexandra Boix de Jesus and Hy B. Dao and Anthony Imani and Gabriel A. Rodriguez and Michael S. Shehata and Rachana R. Chandran and Stuart A. Fine and Sin Y. Lim and Michelle To and Serena Y. Lofftus and Nicolas Pedroncelli and Fritz C. Eilber and Brigitte N. Gomperts and Tyler R. McCaw and Cristina Puig-Saus and Joseph G. Crompton},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1910235},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1910235/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells
AU - Alexandra Boix de Jesus
AU - Hy B. Dao
AU - Anthony Imani
AU - Gabriel A. Rodriguez
AU - Michael S. Shehata
AU - Rachana R. Chandran
AU - Stuart A. Fine
AU - Sin Y. Lim
AU - Michelle To
AU - Serena Y. Lofftus
AU - Nicolas Pedroncelli
AU - Fritz C. Eilber
AU - Brigitte N. Gomperts
AU - Tyler R. McCaw
AU - Cristina Puig-Saus
AU - Joseph G. Crompton
PY - 2026
DA - 2026/10/16
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1910235
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1910235/full
AB - Adoptive T-cell therapies using chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) have transformed cancer treatment but remain limited by poor persistence and progressive T-cell exhaustion. Manufacturing strategies that promote memory T-cell formation may improve therapeutic durability. Here we investigated whether transient pharmacologic activation of the p53 pathway influences the differentiation and function of human CD8+ T cells. p53 expression was minimal in quiescent naïve CD8+ T cells but was rapidly induced following T-cell receptor activation. Pharmacologic inhibition of the p53 negative regulator MDM2 increased p53 protein levels and promoted expansion of central memory and stem-like memory T-cell subsets during clonal proliferation. Treated cells displayed enhanced mitochondrial fitness, increased polyfunctional cytokine production, and transcriptional programs consistent with memory differentiation and reduced exhaustion. Importantly, TCR-engineered CD8+ T cells generated in the presence of the MDM2 inhibitor Navtemadlin demonstrated superior tumor-cell killing in vitro compared with conventionally manufactured cells. These findings identify transient p53 activation as a pharmacologic strategy to enhance memory programming during T-cell manufacturing and suggest a clinically feasible approach to improve the efficacy of adoptive T-cell immunotherapies.
SN - 1664-3224
ER -