Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Allogeneic 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 of B2M triggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligands CD54 and CD58 on targets cells robustly dampens NK cell reactivity across all sub-populations. Genetic deletion of CD54 and CD58 in B2M-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 cells in vitro and in vivo without 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. ### Competing Interest Statement KJM is a consultant and has research support from Fate Therapeutics. KJM has research support from Oncopeptides. KJM and QH are consultants at Vycellix. All relationships has been approved by Oslo University Hospital, University of Oslo and Karolinska Institute. RM, EV, YP, MJ, BG, RA, TL, AW, JPG and BV are employees at Fate Therapeutics. MSK has licensed IP (unrelated to this study) to Fate Therapeutics and MS receives research support (for unrelated studies) from Fate Therapeutics.