Kurzfassung

Adoptive transfer of genetically modified T lymphocytes with tumor antigen-specific receptors has proven efficacy in cancer immunotherapy. However, in many patients the overall benefit is still limited due to various tumor escape mechanisms. Cell damage and metabolic/hypoxic stress in the tumor microenvironment can lead to a dysfunctional anti-tumor T cell response called T cell senescence. The tumor suppressor TP53 is a master molecule in the regulation of cell cycle and senescence. Few...Adoptive transfer of genetically modified T lymphocytes with tumor antigen-specific receptors has proven efficacy in cancer immunotherapy. However, in many patients the overall benefit is still limited due to various tumor escape mechanisms. Cell damage and metabolic/hypoxic stress in the tumor microenvironment can lead to a dysfunctional anti-tumor T cell response called T cell senescence. The tumor suppressor TP53 is a master molecule in the regulation of cell cycle and senescence. Few studies have demonstrated the critical role of the p53 isoforms in the regulation of cellular senescence mainly in tumor cells. However, their role in tumor infiltrating lymphocytes (TILs) remains largely unexplored. In this project, we will interrogate the cellular phenotype as well as the effector function of human T cells simultaneously engineered with defined p53 isoforms and a tumor antigen-specific T-cell receptor (TCR).
Preliminary characterization studies revealed less senescence-associated markers, a stronger cytokine release and enhanced tumor-specific killing capacity in vitro of p53 isoforms-engineered T cells. Additionally, first comparative analyses between p53 isoform-modified and control T-cells revealed changes in the cell’s metabolic program and energetic phenotype. Therefore, the studies included in this proposal will 1) further analyze the bioenergetic profiles of these T cells, with a particular focus on the glycolytic and mitochondrial metabolic activities, 2) validate the findings in xenograft mouse models of adoptive immunotherapy. By providing insights in the regulation of T cell functions, metabolic changes and underlying mechanisms that limit immunosenescence, genetic modification with p53 isoforms could be a promising strategy to circumvent tumor-mediated T cell dysfunction and represents a novel approach with high potential for cancer immunotherapy.
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