Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity

Background Tumor microenvironment-associated T cell senescence is a key limiting factor for durable effective cancer immunotherapy. A few studies have demonstrated the critical role of the tumor suppressor TP53-derived p53 isoforms in cellular senescence process of non-immune cells. However, their role in lymphocytes, in particular tumor-antigen (TA) specific T cells remain largely unexplored. Methods Human T cells from peripheral blood were retrovirally engineered to coexpress a TA-specific T cell receptor and the Delta 133p53 alpha-isoform, and characterized for their cellular phenotype, metabolic profile and effector functions. Results Phenotypic analysis of Delta 133p53 alpha-modified T cells revealed a marked reduction of the T-cell inhibitory molecules (ie, CD160 and TIGIT), a lower frequency of senescent-like CD57(+) and CD160(+) CD8(+) T cell populations, and an increased number of less differentiated CD28(+) T cells. Consistently, we demonstrated changes in the cellular metabolic program toward a quiescent T cell state. On a functional level, Delta 133p53 alpha-expressing T cells acquired a long-term proliferative capacity, showed superior cytokine secretion and enhanced tumor-specific killing in vitro and in mouse tumor model. Finally, we demonstrated the capacity of Delta 133p53 alpha to restore the antitumor response of senescent T cells isolated from multiple myeloma patients. Conclusion This study uncovered a broad effect of Delta 133p53 alpha isoform in regulating T lymphocyte function. Enhancing fitness and effector functions of senescent T cells by modulation of p53 isoforms could be exploited for future translational research to improve cancer immunotherapy and immunosenescence-related diseases.

Automated summary

This study revealed a broad effect of the Delta 133p53 alpha isoform in regulating T lymphocyte function. Enhancing the fitness and effector functions of senescent T cells by modulating p53 isoforms could be utilized for future translational research to improve cancer immunotherapy and immunosenescence-related diseases.