Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies.

Hammer Q, Perica K, Mbofung RM, van Ooijen H, Martin KE, Momayyezi P, Varady E, Pan Y, Jelcic M, Groff B, Abujarour R, Krokeide SZ, Lee T, Williams A, Goodridge JP, Valamehr B, Önfelt B, Sadelain M, Malmberg KJ

Cell Stem Cell 31 (9) 1376-1386.e8 [2024-09-05; online 2024-07-08]

Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing of beta-2 microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection by the host, although the absence of B2M is expected to trigger missing-self responses by host natural killer (NK) cells. Here, we demonstrate that genetic deletion of the adhesion ligands CD54 and CD58 in B2M-deficient chimeric antigen receptor (CAR) T cells and multi-edited induced pluripotent stem cell (iPSC)-derived CAR NK cells reduces their susceptibility to rejection by host NK cells in vitro and in vivo. The absence of adhesion ligands limits rejection in a unidirectional manner in B2M-deficient and B2M-sufficient settings without affecting the antitumor functionality of the engineered donor cells. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection by host immune cells, facilitating the implementation of universal immunotherapy.

PubMed 38981470

DOI 10.1016/j.stem.2024.06.011

Crossref 10.1016/j.stem.2024.06.011

mid: NIHMS2008475
pmc: PMC12718542
pii: S1934-5909(24)00219-4