美国宾夕法尼亚大学Saar Gill课题组研制了用于癌症免疫治疗的人类嵌合抗原受体（CAR）巨噬细胞。2020年3月23日出版的《自然-生物技术》在线发表了这项成果。
基于巨噬细胞独特的效应子功能及其穿透肿瘤的能力，研究人员用CAR对人类巨噬细胞进行了基因工程改造，以指导其对肿瘤的吞噬活性。研究发现，嵌合腺病毒载体克服了人巨噬细胞对基因操纵的固有抵抗力，并赋予其持续的促炎（M1）表型。 在体外CAR巨噬细胞（CAR-Ms）显示出抗原特异性吞噬作用和肿瘤清除率。
在两个实体瘤异种移植小鼠模型中，单次使用人CAR-M可减少肿瘤负荷并延长总体生存期。CAR-M活性的特征表明，CAR-M表达促炎的细胞因子和趋化因子，将M2巨噬细胞转化为M1、上调抗原呈递机制、募集抗原并将其呈递给T细胞，并抵抗免疫抑制细胞因子的作用。在人源化小鼠模型中，CAR-Ms进一步显示出可诱导的促炎肿瘤微环境并增强抗肿瘤T细胞的活性。
据悉，CAR-T细胞疗法已在血液系统恶性肿瘤中显示出应用前景，但其在实体瘤中的应用一直具有挑战。
附：英文原文
Title: Human chimeric antigen receptor macrophages for cancer immunotherapy
Author: Michael Klichinsky, Marco Ruella, Olga Shestova, Xueqing Maggie Lu, Andrew Best, Martha Zeeman, Maggie Schmierer, Konrad Gabrusiewicz, Nicholas R. Anderson, Nicholas E. Petty, Katherine D. Cummins, Feng Shen, Xinhe Shan, Kimberly Veliz, Kristin Blouch, Yumi Yashiro-Ohtani, Saad S. Kenderian, Miriam Y. Kim, Roddy S. OConnor, Stephen R. Wallace, Miroslaw S. Kozlowski, Dylan M. Marchione, Maksim Shestov, Benjamin A. Garcia, Carl H. June, Saar Gill
Issue&Volume: 2020-03-23
Abstract: Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging1,2,3,4. Given the unique effector functions of macrophages and their capacity to penetrate tumors5, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.
DOI: 10.1038/s41587-020-0462-y
Source: https://www.nature.com/articles/s41587-020-0462-y
Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex
本期文章：《自然—生物技术》：Online/在线发表
