Abstract：
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.
摘要：
同种异体细胞免疫疗法具有广泛的临床应用前景，但由于宿主免疫系统对供体细胞的潜在排斥而面临局限性。β-2微球蛋白（B2M）表达的沉默通常用于逃避宿主T细胞介导的排斥反应，尽管B2M的缺失预计会触发宿主自然杀伤（NK）细胞的自身缺失反应。这里,我们证明,B2M缺陷型嵌合抗原受体(CAR)T细胞和多重编辑诱导多能干细胞(iPSC)衍生的CARNK细胞中粘附配体CD54和CD58的基因缺失降低了它们在体外和体内对宿主NK细胞排斥反应的易感性.粘附配体的不存在限制了在B2M缺陷和B2M充足设置中以单向方式的排斥,而不影响工程化供体细胞的抗肿瘤功能。因此，这些数据表明，粘附配体的遗传消融有效地减轻了宿主免疫细胞的排斥反应，促进普遍免疫疗法的实施。
