Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA.
Sana Biotechnology, Inc., South San Francisco, CA.
J Exp Med. 2021 Mar 1;218(3). doi: 10.1084/jem.20200839.
Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.
在这里，我们报告了免疫检查点信号调节蛋白 α（SIRPα）在 NK 细胞中的存在和功能，并描述了如何对其进行调节以用于细胞治疗。IL-2 刺激可上调 NK 细胞 SIRPα，以依赖于阈值的方式与靶细胞 CD47 相互作用，并拮抗其他刺激信号，包括 IL-2、CD16 或 NKG2D。CD47 的高表达可保护 K562 肿瘤细胞和鼠和人 MHC I 缺陷靶细胞免受 SIRPα+NK 细胞的攻击，但不能免受 SIRPα-NKL 或 NK92 细胞的攻击。SIRPα 缺陷或抗体阻断增加了 NK 细胞的杀伤能力。在异种环境中，人 MHC 缺陷细胞中猴 CD47 的过表达可防止恒河猴 NK 细胞的细胞毒性。SIRPα-CD47 轴被发现具有高度的种属特异性。综上所述，这些结果表明，破坏 SIRPα-CD47 免疫检查点可能增强 NK 细胞的抗肿瘤反应，而 CD47 的高表达可能防止 NK 细胞对同种异体和异种组织的杀伤。
