Human iPSC-derived NK cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D complex enhance anti-solid tumor activity
Studies of chimeric antigen receptor (CAR)-T and -Natural killer (NK) cells have shown promising results in treating hematological malignancies. However, there are still obstacles to effectively treating solid tumors. These include the challenges of CAR-T cell homing and infiltration, the presence of immunosuppressive microenvironments, and the potential for antigen escape in solid tumors. To overcome the known limitations of immune cell therapy, we engineered human induced pluripotent stem cell (hiPSC)-derived NK (eNK) cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D-DAP10 complex. We introduced the six genes into hiPSCs using the piggyBac system and stimulated them to differentiate into NK cells. Overexpression of NKG2D complex and high-affinity CD16 enhanced the antitumor function of the eNK cells. Overexpression of IL-15 prolonged the persistence of the eNK cells in vitro and in vivo. Forced expression of CCR2B enhanced eNK cell tumor infiltration. Forced expression of CCL19 endowed the eNK cells with the ability to recruit dendritic cells. We found that the eNK cells were able to lyse HLA-E-expressing tumor cells, but not normal human cells. These proof-of-concept studies demonstrate the promise of our eNK cells as a novel adoptive cell therapy product for the treatment of solid tumors. Overall design: To enhance antitumor activity of NK cells against solid tumors, we generated NK cells derived from gene-engineered hiPSC forced expression of CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D-DAP10 complex. To evaluate the effect of transgene integration, we performed comparative gene expression analysis using data obtained from RNA-seq of non-engineered and engineered hiPSCs. Comparative gene expression profiling analysis of RNA-seq data for non-engineered and engineered hiPSCs.