deletion improves the therapeutic potential of adoptively transferred NK cells.

BACKGROUND

To enhance the efficacy of adoptive NK cell therapy against solid tumors, NK cells must be modified to resist exhaustion in the tumor microenvironment (TME). However, the molecular checkpoint underlying NK cell exhaustion in the TME remains elusive.

METHODS

We analyzed the correlation between expression and NK cell functional exhaustion in the TME both in humans and mice by single-cell transcriptomic analysis and by using gene reporter mice. We investigated the effects of deletion on adoptively transferred NK cell therapy against cancers by using NK cells from NK-specific deficient mice or peripheral blood-derived or induced pluripotent stem cell (iPSC)-derived human NK cells with deletion by CRISPR/Cas9. We also investigated the potential synergy of double deletion of and another checkpoint molecule, .

RESULTS

By single-cell transcriptomic analysis and by using gene reporter mice, we found that expression correlated with NK cell exhaustion in the TME both in humans and mice and that the NK cell subset correlated with poorer survival of tumor patients. deletion promoted the antitumor activity of adoptively transferred mouse NK cells and adoptively transferred human NK cells, either derived from peripheral blood or differentiated from iPSCs. deletion rendered NK cells with elevated capacities for tumor infiltration and effector functions. deletion also synergized with deletion to further improve antitumor activity in vivo.

CONCLUSIONS

This study highlighted TIPE2 targeting as a promising approach for enhancing adoptive NK cell therapy against solid tumors.