中国医学科学院北京协和医学院附属医院血液病研究所Tao Cheng，Jianxiang Wang，Jun Shen和中山大学Xin Li共同合作，近期取得重要工作进展。他们研究提出，激活先天免疫反应可使hPSC来源的CAR巨噬细胞重新极化以提高抗肿瘤活性。相关研究成果2024年5月8日在线发表于《细胞—干细胞》杂志上。

据介绍，从人多能干细胞（hPSC）产生嵌合抗原受体巨噬细胞（CAR-Ms）为癌症免疫疗法提供了新的前景，但目前存在分化效率低和功能有限的挑战。

研究人员开发了一种高效的基于单层的系统，该系统可以在3周内从单个hPSC中产生约6000个巨噬细胞。基于CAR结构筛选，研究人员在体外产生了具有稳定CAR表达和强效抑瘤活性的hPSC-CAR-M。为了克服hPSC-CAR-Ms在体内的抑瘤活性损失，研究人员使用干扰素-γ和单磷酸脂质A来激活先天免疫反应，使hPSC-CAR-Ms重新极化以抑瘤巨噬细胞。

此外，通过hPSC-CAR-Ms对T细胞的联合激活，研究人员证明激活协同的先天适应性免疫反应可以进一步增强hPSC-CAR-Ms在体内的抗肿瘤作用。

总之，这一研究为显著提高hPSC-CAR-Ms的生产和功能提供了可行的方法，以支持其转化为临床应用。

附：英文原文

Title: Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity

Author: Jun Shen, Shuzhen Lyu, Yingxi Xu, Shuo Zhang, Li Li, Jinze Li, Junli Mou, Leling Xie, Kejing Tang, Wei Wen, Xuemei Peng, Ying Yang, Yu Shi, Xinjie Li, Min Wang, Xin Li, Jianxiang Wang, Tao Cheng

Issue&Volume: 2024-05-08

Abstract: Generation of chimeric antigen receptor macrophages (CAR-Ms) from human pluripotentstem cells (hPSCs) offers new prospects for cancer immunotherapy but is currentlychallenged by low differentiation efficiency and limited function. Here, we developa highly efficient monolayer-based system that can produce around 6,000 macrophagesfrom a single hPSC within 3 weeks. Based on CAR structure screening, we generate hPSC-CAR-Mswith stable CAR expression and potent tumoricidal activity in vitro. To overcome the loss of tumoricidal activity of hPSC-CAR-Ms in vivo, we use interferon-γ and monophosphoryl lipid A to activate an innate immune responsethat repolarizes the hPSC-CAR-Ms to tumoricidal macrophages. Moreover, through combinedactivation of T cells by hPSC-CAR-Ms, we demonstrate that activating a collaborativeinnate-adaptive immune response can further enhance the anti-tumor effect of hPSC-CAR-Msin vivo. Collectively, our study provides feasible methodologies that significantly improvethe production and function of hPSC-CAR-Ms to support their translation into clinicalapplications.

DOI: 10.1016/j.stem.2024.04.012

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00139-5