Engineering NK cells for improved functionality in immunotherapy

Cancer survival rates have been steadily increasing over the last century, but many types of cancer remain hard to treat using traditional approaches. Recently, there has been considerable success in using the immune system to combat cancer, but important obstacles remain. Our research group is interested in a specific component of the immune system that is already inherently good at detecting and eliminating both infected and malignant cells, so called natural killer (NK) cells. To harness immune cells such as NK cells to effectively fight cancer they need to fulfil several functions. They need to be able to home to the site of the malignancy, distinguish cancerous cells from normal cells and specifically destroy cancerous cells through the guided release of toxins. NK cells have an inherent ability to detect cancerous cells via recognition receptors which activate them to kill the cancer cell. However, in common with most cells of our body, NK cells undergo a process of maturation in order for them to acquire this functionality. The regulation of NK cell maturation, proliferation, lifespan and tumor homing is still poorly understood. Transcription factors precisely control when a gene is turned on or off and therefore regulate all aspects of cell functionality. We our focused on identifying transcription factors that affect the ability of an NK cell to home to tumors and factors that regulate NK cell maturation and durability. Our ultimate aim is to engineer NK cells so that they can be readily expanded and driven to maturity outside of the body using small numbers of immature cells extracted from donors. We will accomplish this through a variety of methods including cutting-edge genetic manipulation of cells and functional studies using tumor models. We hope that our basic findings can be transferred across to improving cellular NK cell based therapies which are already proving to be an exciting avenue in the treatment of cancer.

Natural killer (NK) cells represent innate lymphoid cells that can identify and kill infected and malignant cells. Taking different approaches, cellular immunotherapy trials have highlighted the efficacy of NK cells for the treatment of cancer. However, widespread use of NK cell regimens are limited by our understanding of the mechanisms controlling NK cell proliferation, differentiation, and function. A deeper molecular understanding of the pathways that govern NK cell differentiation is needed to advance NK cell-based immunotherapies. Capitalising on recent insights gained by our laboratory to transcriptional control of human NK cell differentiation, promising preliminary data, and a strong team of national and international collaborators, we propose innovative strategies to regulate NK cell differentiation, homing and effector functions through genetic modulation of specific transcription factors. We will (1) determine how contextually engineered transcription factor Bcl11b overexpression modulates NK cell differentiation, maturation, function, in vivo persistence and tumor control and (2) define signals that promote Bcl11b expression in NK cells and dissect mechanisms of Bcl11b-driven differentiation. Furthermore, we will (3) study tissue-resident and tumor-infiltrating NK cells in endometrial cancer in order to understand their epigenetic regulation. Based on an original hypothesis, a ground-breaking aspect of our proposal is to device strategies to engineer resilient, tissue-homing NK cells for effective immunotherapy of solid tumors based on single or combinatorial transcription factor engineering. The project is driven by state of the art technologies. The concept and results of the project will provide understanding of how NK cells are transcriptionally regulated, which is of interest in a number of human diseases, and promises to provide novel treatment approaches for adoptive cellular therapy of cancer.