Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 9, Issue 6, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2020-001846
Keywords
cell engineering; immunotherapy; adoptive; receptors; antigen; T-lymphocytes; costimulatory and inhibitory T-cell receptors
Categories
Funding
- Collaborative Research Center 1292 [CRC 1292 TP06]
- German Consortium for Translational Cancer Research (DKTK) Frankfurt/Mainz partner site, Mainz
- Clinician Scientist Fellowship 'TransMed Jumpstart Program' by the Else Kroner Fresenius Foundation [2019_A72]
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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.
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.
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