Reprogramming Natural Killer Cells for Immunotherapy of Cancer

Natural killer (NK) cells, immune cells with an innate ability to recognize and eliminate cancer cells, are powerful immune effectors, owing in large part to their ability to target cancers based on MHC ligand mismatch, thus representing a source of potentially allogeneic immune cells. Despite this, immune function in complex cancers such as aggressive solid tumors is dysregulated, and NK cells in such tumor microenvironments (TME) experience epigenetic, immunological, phenotypic and metabolic dysfunction. The profound immunosuppression in the TME is caused by a number of mechanisms both intrinsic and extrinsic to cancer and immunosuppressive immune cells, which dampens not only NK cell, but also other immune effector responses. Various approaches aimed at restoring NK cell immunometabolic effector responses have leveraged pharmacological and genetic tools to regulate NK cell activation in terms of controlling their anti-tumor function, metabolism and persistence. In this talk, we discuss opportunities for NK cells in immunotherapy, including novel genetic engineering approaches and therapeutic modulation strategies aimed at enhancing NK cell immune responses in the TME, with the ultimate goal to effectively and durably targeting currently uncurable cancers.