Abstract
Abstract Va24-invariant Natural Killer T cells (NKTs) have potent antitumor properties and are being developed for cellular immunotherapy of cancer. Such therapy requires extensive ex vivo expansion of primary NKTs while preserving their longevity and function. However, the mechanism responsible for NKT-cell maintenance remains poorly understood. In this study we analyzed the proliferative potential of human NKT-cell subsets and found that antigen-induced in vitro expansion of primary NKTs is associated with the accumulation of a CD62L-positive subset. Following magnetic sorting, only CD62L-positive cells survived and proliferated in response to TCR-stimulation in vitro. After transfer to NSG mice, CD62L-positive NKTs persisted 5 times longer and had higher therapeutic efficacy in a lymphoma model compared with CD62L-negative NKTs. Proliferating CD62L-positive cells downregulated or maintained CD62L expression when they were activated via TCR alone or in combination with co-stimulatory receptors, respectively. After testing 161 clones of K562 cells, genetically modified to express CD1d and various combinations of co-stimulatory molecules, we selected the B-8-2 clone (HLAnullCD1dmedCD86high4-1BBmedOX40Lmed) which induced the highest rate of NKT-cell expansion with the preservation of CD62L-positive cells. Compared with NKTs expanded with autologous PBMC, those expanded with B-8-2 exhibited a prolonged in vivo persistence and superior antitumor activity. Thus, our results reveal a previously unanticipated functional hierarchy in human NKTs that can be exploited for cancer immunotherapy.
Published Version
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