Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies,Cell Stem Cell

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Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-07-08 , DOI: 10.1016/j.stem.2024.06.011
Quirin Hammer ₁ , Karlo Perica ₂ , Rina M Mbofung ₃ , Hanna van Ooijen ₄ , Karen E Martin ₅ , Pouria Momayyezi ₁ , Erika Varady ₃ , Yijia Pan ₃ , Mark Jelcic ₃ , Brian Groff ₃ , Ramzey Abujarour ₃ , Silje Z Krokeide ₅ , Tom Lee ₃ , Alan Williams ₃ , Jode P Goodridge ₃ , Bahram Valamehr ₃ , Björn Önfelt ₆ , Michel Sadelain ₇ , Karl-Johan Malmberg ₈

Affiliation

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Department of Medicine, Weill Cornell Medical College, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Fate Therapeutics, Inc., San Diego, CA, USA.
Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden.
Precision Immunotherapy Alliance, Institute for Cancer Research, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Precision Immunotherapy Alliance, Institute for Cancer Research, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

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.

中文翻译：

粘附配体的基因消融减轻了同种异体细胞免疫疗法的排斥反应

同种异体细胞免疫疗法有望广泛应用于临床，但由于宿主免疫系统可能排斥供体细胞，因此面临局限性。 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 的缺失预计会引发宿主自然杀伤 (NK) 细胞的自我缺失反应。在这里，我们证明，在 B2M 缺陷的嵌合抗原受体 (CAR) T 细胞和多重编辑的诱导多能干细胞 (iPSC) 衍生的 CAR NK 细胞中，粘附配体 CD54 和 CD58 的遗传删除降低了它们对宿主 NK 排斥的敏感性体外和体内的细胞。粘附配体的缺失限制了 B2M 缺陷和 B2M 充足环境中单向方式的排斥，而不影响工程供体细胞的抗肿瘤功能。因此，这些数据表明粘附配体的基因消除有效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。

更新日期：2024-07-08

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