瑞典卡罗林斯卡学院Karl-Johan Malmberg和Quirin Hammer共同合作，近期取得重要工作进展。他们研究提出，粘附配体的基因沉默可减轻同种异体细胞免疫疗法的排斥反应。相关研究成果2024年7月8日在线发表于《细胞—干细胞》杂志上。

据介绍，同种异体细胞免疫疗法有望在临床上广泛应用，但由于宿主免疫系统对供体细胞的潜在排斥作用而面临限制。β-2微球蛋白（B2M）的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的缺失预计会引发宿主自然杀伤（NK）细胞缺失的自我缺失反应。

研究人员证明了B2M缺陷嵌合抗原受体（CAR）T细胞和多编辑诱导多能干细胞（iPSC）来源的CAR NK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细胞排斥的易感性。在B2M缺乏和B2M充足的环境中，粘附配体的缺乏以单向方式限制排斥反应，而不影响工程供体细胞的抗肿瘤功能。

因此，这一研究数据表明，粘附配体的基因消融有效地减轻了宿主免疫细胞的排斥反应，促进了通用免疫疗法的实施。

附：英文原文

Title: Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies

Author: Quirin Hammer, Karlo Perica, Rina M. Mbofung, Hanna van Ooijen, Karen E. Martin, Pouria Momayyezi, Erika Varady, Yijia Pan, Mark Jelcic, Brian Groff, Ramzey Abujarour, Silje Z. Krokeide, Tom Lee, Alan Williams, Jode P. Goodridge, Bahram Valamehr, Bjrn nfelt, Michel Sadelain, Karl-Johan Malmberg

Issue&Volume: 2024-07-08

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.

DOI: 10.1016/j.stem.2024.06.011

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00219-4