Enhancing Anti-Tumor Activity of Natural Killer Cells by Upregulating Amino Acid Transporters

Abstract

Abstract In spite of the superior efficacy of NK cells against hematological cancers such as acute myeloid leukemia (AML), the poor ability of NK cells to infiltrate solid tumors, such as breast cancer or colorectal carcinoma, limits the potential NK cells for cancer immunotherapy. Diverse approaches are now being undertaken to overcome this limitation by modifying NK cells for better recognition and effector function of NK cells. One of the efforts is to genetically engineer NK cells to express chimeric antigen receptors (CARs) for new tumor recognition and migration to the tumor, resulting in enhanced tumor killing. Here, we propose to enhance the anti-tumor activity of natural killer cells by upregulating amino acid transporters. Our laboratory recently showed that the upregulation of amino acid transporter is correlated with enhanced NK cell effector function. In particular, the upregulation of leucine amino acid transporter, CD98/LAT1, can induce leucine-driven mTORC1 activation and metabolic transformation, leading to enhanced proliferation and effector function of NK cells. Therefore, we will enhance the metabolism of NK cells by genetically modifying to upregulate the CD98/LAT1 nutrient transporter and make them more potent and sustained in vivo. In order to be the players in anti-tumor immunity, NK cells need to survive in the metabolically hostile conditions of the tumor microenvironment, where they have to compete for nutrients with metabolically active cancerous cells. We expect that combing our approach to augmenting the metabolism of NK cells with enhanced tumor recognition of CAR-NK cells could maximize the efficacy of cancer immunotherapy.