Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Abstract

SUMMARYAllogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection, although absence ofB2Mtriggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligandsCD54andCD58on targets cells robustly dampens NK cell reactivity across all sub-populations. Genetic deletion ofCD54andCD58inB2M-deficient allogeneic chimeric antigen receptor (CAR) T and multi-edited induced pluripotent stem cell (iPSC)-derived NK cells reduces their susceptibility to rejection by NK cellsin vitroandin vivowithout affecting their anti-tumor effector potential. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection of allogeneic immune cells for immunotherapy.