VITNK - deciphering vitamin A and D regulation of human NK cells for cellular immunotherapy

ongoing

Natural killer (NK) cells are cytotoxic innate immune cells that defend against viral infections and cancer. As cancer is one of the leading causes of death worldwide, more effective treatment options are urgently needed. Harnessing NK cell cytotoxicity for cancer treatment shows promise, but there is still room for improvement, particularly against solid tumours, which are difficult to treat due to challenges such as limited tumour infiltration. Therefore, identifying targetable factors that enhance not only NK cell development, function, expansion and persistence, but also homing and migration are crucial to optimize cancer immunotherapies. Vitamin metabolites retinoic acid (RA) and calcitriol (CA) activate nuclear receptors (RAR, RXR, VDR) and regulate differentiation, function and homing properties of T cells and ILCs. In the VITNK project, I will systematically investigate how RA and CA as well as their nuclear receptors impact human NK cell development, differentiation, function, expansion, survival, and migration. To achieve this, haematopoietic stem cell-based NK cell differentiation cultures and short-term peripheral blood mature NK cell cultures will be used. In-depth analysis of the changes induced by vitamin metabolite supplementation and CRISPR-mediated nuclear receptor knockout using advanced cell-based assays in combination with cutting-edge single cell RNA, ATAC- and ChIP-sequencing will give a comprehensive insight into the molecular mechanisms that are governed by vitamin A and D in human NK cells. VITNK will thus establish how vitamin A and D modulate NK cell homing and migration, which is essential for efficient tumour infiltration. The purpose of VITNK is to take initial preclinical steps towards therapeutic targeting by thoroughly evaluating the potential of vitamin A and/or D to upgrade NK cell-based immunotherapy for solid tumours, paving a way for my future research career.