Lysosomal Remodelling in Natural Killer Cells – New Targets for Immune-Gene Therapy

The key role for natural killer (NK) cells in the host response to virus infected or transformed cells is well known.

A central biological process underlying the ability of NK cells to kill target cells is their functional tuning against self-MHC in a process referred to as NK cell education.

However, the intracellular mechanism for functional tuning by surface receptors during NK cell education remains a key knowledge gap.

Understanding how NK cells “remember” their NK cell education to deliver fine-tuned functional responses is critical to developing new NK-cell-based therapies against cancer.

My group recently discovered that NK cell education is associated with structural remodeling of dense-core secretory lysosomes.

In this project we will use a combination of cutting-edge technologies, including single-cell RNA sequencing, imaging, mass cytometry and CRISPR/Cas9-editing of primary NK cells and induced pluripotent stem cell (iPSC)-derived NK cells to test the hypothesis that signaling from acidic Ca2+ stores is a central element of NK cell education and can be harnessed in cell therapy.

By deciphering the biochemical and genetic pathways that determine qualitative aspects of NK cell function through lysosomal loading/reloading, the outlined research holds promise to identify new targets for immune and gene therapy.

Such advances will feed directly into our established NK cell therapy pipeline with strong academic and industrial partnerships within and outside the EU.