Genetic engineering to enhance NK cell effector function against tumors and viruses at single cell resolution
Equipping immune cells with improved therapeutic response programs is an emerging field for clinical application. Enhancing the function of immune cells with tools of synthetic immunology not only results in the execution of direct immune actions, but also to the mobilization of other components of the immune system.
The genetic engineering of T cells with chimeric antigen receptors (CARs) has revolutionized current clinical treatment protocols. CAR-T cells not only lead to the destruction of tumor cells, but also might destroy healthy tissue cells causing side effects. Thus, engineering additional cell types such as Natural Killer (NK) cells, a type of innate immune cells exerting anti-tumor cytotoxicity without causing graft versus host disease, holds great promise. NK cells fight at the forefront of immunity against pathogens and cancer. NK cell activity is regulated by a delicate balance of inhibitory and activating signals delivered by specialized receptors. In chronic viral disease and cancer, NK cells display a dysfunctional phenotype characterized by low expression of activating signals and high expression of inhibitory signals. Thus, for therapeutic application it will be instrumental to equip NK cells with additional force to overcome dysfunction. Since NK cells represent a heterogeneous population, the identification of NK subsets with high effector potential will be highly relevant to select the most powerful-engineered NK cells for clinical application.
Our interdisciplinary project (Figure 1) combines the expertise of Adelheid Cerwenka, a basic immunologist, Sonja Loges, a translational oncologist and Joachim Spatz, a material scientist and biophysicist. Here, we will i. refine methods of genetic engineering of primary human NK cells and identify the most relevant hubs for NK cell harnessing ii. retarget NK cells to tumor cells using CAR technology iii. assess NK cell anti-tumor reactivity quantitatively at the single cell level to select and multiply the most potent NK cell population for potential therapy. The platform will be adaptable to different cancer entities and to virus infection models.
