Adoptive cellular therapy using T cells engineered to recognize tumour-associated antigens or neoantigens following expression of chimeric-antigen receptor (CAR) or T cell-receptor (TCR) encoding genes has advanced as a promising and personalized immunotherapy for chemo-refractory leukemia and solid cancer. However, fitness of infused tumour antigen receptor-engineered T cells and their capacity to resist the suppressive tumour microenvironment-driven T cell senescence (differentiated dysfunctional state) is key for a durable effective cancer immunotherapy. 

Cellular senescence displays a state of permanent proliferation arrest. Increasing numbers of senescent T cells are associated with many pathological conditions, such as cancer, infection, autoimmunity or cardiovascular and neurodegenerative diseases. The tumour suppressor p53 is a master molecule in response to cell damage. It regulates in a complex network with 12 identified p53 isoforms the expression of many genes and is involved in cellular senescence in non-immune cells. However, the function of senescence-related p53 isoforms in T lymphocytes in the context of immune related disorders or cancer remains unexplored. 

The team reported for the first time that ?133p53? isoform functions as a novel unappreciated transcriptional regulator of metabolic and cellular fitness by promoting effective phenotype and properties of tumour-antigen specific human cytotoxic T cells. The study demonstrated that ?133p53?-engineered human T cells remain in a less differentiated phenotype with a reduced expression of T-cell inhibitory immune checkpoint receptors, i.e. PD-1 and TIGIT, and a lower frequency of senescent-like CD57+ and an increased number of more juvenile CD28+ CD8+ T cells. On a functional level, modified T cells were less sensitive to apoptosis, acquired a long-term proliferative capacity, showed superior cytokine secretion and enhanced tumour-specific killing potential in vitro and in a xenograft osteosarcoma tumour model.  The study also uncovered a role of ?133p53? isoform in metabolic reprogramming of TCR-equipped T cells towards a quiescent state less prone to replicative cellular senescence. Importantly, the authors could demonstrate the functional relevance of ?133p53? by restoring effector functions of dysfunctional/senescent T cells isolated from myeloma cancer patients. 

In conclusion, circumventing replicative cellular senescence in antigen receptor-redirected T cells by overexpressing ?133p53? provides a promising strategy to improve robustness and resilience of anti-tumour responses with a broad potential application beyond cancer immunotherapy, including chronic infection, autoimmunity and immunosenescence-related diseases. 

This work, supported by the Collaborative Research Center 1292 and the TransMed Jumpstart Program: 2019_A72' (supported by the Else Kröner Fresenius Foundation) was published in the Journal of Immunotherapy of Cancer. 

Legscha KJ et al., ?133p53? enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity. J Immunother Cancer. 2021 Jun;9(6):e001846. DOI: 10.1136/jitc-2020-001846 

Contact: 
Dr. Hakim Echchannaoui 
Department of Hematology, Oncology, and Pneumology 
University Medical Center 
Obere Zahlbacher Straße 63 
D-55131 Mainz, Germany 
phone +49 6131 17-9722 
email: echchann@uni-mainz.de