美国斯坦福大学Crystal L. Mackall研究小组发现，工程化CD47可保护T细胞来增强抗肿瘤免疫力。2024年5月15日，《自然》杂志在线发表了这项成果。

研究人员将抗CD47抗体与过继转移T细胞结合使用，目的是提高抗肿瘤疗效，但观察到由于巨噬细胞介导的表达嵌合抗原受体（CAR）或工程化T细胞受体的T细胞的快速清除，治疗效果减弱。抗CD47抗体介导的CAR T细胞清除既有效又迅速，足以作为有效的安全开关。为了克服这一挑战，研究人员设计了CD47变体CD47(Q31P)（47_E），它能与SIRPα结合，并提供一个不会被抗CD47抗体阻断的“别吃我”信号。表达47_E的TCR或CAR T细胞经抗CD47抗体处理后能抵抗巨噬细胞的清除，并能介导大量、持续的巨噬细胞被招募到肿瘤微环境中。

虽然许多被招募的巨噬细胞表现出M2样特征，但联合疗法协同增强了抗肿瘤疗效。该研究确定了巨噬细胞是T细胞持久性的主要调节因子，并说明了将T细胞导向疗法与旨在激活巨噬细胞的疗法相结合所面临的基本挑战。它提供了一种能够同时利用T细胞和巨噬细胞抗肿瘤作用的治疗方法，并增强了对实体瘤的疗效。

据介绍，过继转移的T细胞和阻断CD47-SIRPα轴的药物是很有前景的癌症疗法，它们能激活免疫系统的不同臂。

附：英文原文

Title: Engineered CD47 protects T cells for enhanced antitumour immunity

Author: Yamada-Hunter, Sean A., Theruvath, Johanna, McIntosh, Brianna J., Freitas, Katherine A., Lin, Frank, Radosevich, Molly T., Leruste, Amaury, Dhingra, Shaurya, Martinez-Velez, Naiara, Xu, Peng, Huang, Jing, Delaidelli, Alberto, Desai, Moksha H., Good, Zinaida, Polak, Roel, May, Audre, Labanieh, Louai, Bjelajac, Jeremy, Murty, Tara, Ehlinger, Zach, Mount, Christopher W., Chen, Yiyun, Heitzeneder, Sabine, Marjon, Kristopher D., Banuelos, Allison, Khan, Omair, Wasserman, Savannah L., Spiegel, Jay Y., Fernandez-Pol, Sebastian, Kuo, Calvin J., Sorensen, Poul H., Monje, Michelle, Majzner, Robbie G., Weissman, Irving L., Sahaf, Bita, Sotillo, Elena, Cochran, Jennifer R., Mackall, Crystal L.

Issue&Volume: 2024-05-15

Abstract: Adoptively transferred T cells and agents designed to block the CD47–SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a ‘don’t eat me’ signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

DOI: 10.1038/s41586-024-07443-8

Source: https://www.nature.com/articles/s41586-024-07443-8