Visual Universitätsmedizin Mainz

26. July 2021

A novel approach to enhance metabolic and cellular fitness of tumour antigen-specific T cells for cancer immunotherapy

Scientists from the research group of Prof. Dr. Matthias Theobald (Department of Internal Medicine III) at the Mainz University Medical Center have uncovered the potential of the tumour suppressor p53-derived Δ133p53α isoform as a novel gatekeeper of T cell fitness and resilience for adoptive cancer immunotherapy.

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 Δ133p53α 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 Δ133p53α-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 Δ133p53α 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 Δ133p53α 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 Δ133p53α 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., Δ133p53α 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