通过 Δ133p53α 调控 p53 信号网络增强 CAR-T 细胞治疗

Chimeric antigen receptor (CAR) T cell dysfunction is a major barrier to achieving lasting remission in hematologic cancers, especially in chronic lymphocytic leukemia (CLL).

We have shown previously that 133p53 , an endogenous isoform of the human TP53 gene, decreases in expression with age in human T cells, and that reconstitution of 133p53 in poorly functional T cells can rescue proliferation [A. M. Mondal et al. , J. Clin. Invest. 123 , 5247-5257 (2013)]. Although 133p53 lacks a transactivation domain, it can form heterooligomers with full-length p53 and modulate the p53-mediated stress response [I. Horikawa et al. , Cell Death Differ. 24 , 1017-1028 (2017)].

Here, we show that constitutive expression of 133p53 potentiates the anti-tumor activity of CD19-directed CAR T cells and limits dysfunction under conditions of high tumor burden and metabolic stress.

We demonstrate that 133p53 -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 133p53 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 133p53 may represent a translationally viable strategy for improving CAR T cell therapy.