Enhancing chimeric antigen receptor T cell therapy by modulating the p53 signaling network with Δ133p53α

• 成果类型: Article
• 署名作者: Roselle, Christopher; Horikawa, Izumi; Chen, Linhui; Kelly, Andre R.; Gonzales, Donna; Da, Tong; Wellhausen, Nils; Rommel, Philipp C.; Baker, Daniel; Suhoski, Megan; Scholler, John; O'Connor, Roddy S.; Young, Regina M.; Harris, Curtis C.; June, Carl H.
• 署名单位: University of Pennsylvania; University of Pennsylvania; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of Pennsylvania; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14703
• DOI: 10.1073/pnas.2317735121
• 发表日期: 2024-03-05
• 关键词: isoforms; senescence; protein; death

摘要

Chimeric antigen receptor (CAR) T cell dysfunction is a major barrier to achieving lasting remission in hematologic cancers, especially in chronic lymphocytic leukemia (CLL). have shown previously that A133p53 alpha, an endogenous isoform of the human TP53 gene, decreases in expression with age in human T cells, and that reconstitution of A133p53 alpha in poorly functional T cells can rescue proliferation [A. M. Mondal et al., J. Clin. Invest. 123, 5247-5257 (2013)]. Although A133p53 alpha lacks a transactivation domain, it can form heterooligomers with full- length p53 and modulate the p53- mediated stress response Horikawa et al., Cell Death Differ. 24, 1017-1028 (2017)]. Here, we show that constitutive expression of A133p53 alpha potentiates the anti - tumor activity of CD19- directed CAR T cells and limits dysfunction under conditions of high tumor burden and metabolic stress. demonstrate that A133p53 alpha-expressing CAR T cells exhibit a robust metabolic phenotype, maintaining the ability to execute effector functions and continue proliferating under nutrient- limiting conditions, in part due to upregulation of critical biosynthetic processes and improved mitochondrial function. Importantly, we show that our strategy to constitutively express A133p53 alpha improves the anti - tumor efficacy of CAR T cells generated from CLL patients that previously failed CAR T cell therapy. More broadly, our results point to the potential role of the p53- mediated stress response in limiting the prolonged antitumor functions required for complete tumor clearance in patients with high disease burden, suggesting that modulation of the p53 signaling network with A133p53 alpha represent a translationally viable strategy for improving CAR T cell therapy.