具有抗肿瘤效果的第二代M1极化CAR巨噬细胞

SCI

7 December 2023

A second-generation M1-polarized CAR macrophage with antitumor efficacy

 (Nat Immunol, IF: 31.25)

Lei A, Yu H, Lu S, et al. A second-generation M1-polarized CAR macrophage with antitumor efficacy[J]. Nature Immunology, 2023: 1-15.

Chimeric antigen receptor (CAR) T cell therapies have successfully treated hematological malignancies. Macrophages have also gained attention as an immunotherapy owing to their immunomodulatory capacity and ability to infiltrate solid tumors and phagocytize tumor cells. The first-generation CD3ζ-based CAR-macrophages could phagocytose tumor cells in an antigen-dependent manner. Here we engineered induced pluripotent stem cell-derived macrophages (iMACs) with toll-like receptor 4 intracellular toll/IL-1R (TIR) domain-containing CARs resulting in a markedly enhanced antitumor effect over first-generation CAR-macrophages. Moreover, the design of a tandem CD3ζ-TIR dual signaling CAR endows iMACs with both target engulfment capacity and antigen-dependent M1 polarization and M2 resistance in a nuclear factor kappa B (NF-κB)-dependent manner, as well as the capacity to modulate the tumor microenvironment. We also outline a mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we provide a second-generation CAR-iMAC with an ability for orthogonal phagocytosis and polarization and superior antitumor functions in treating solid tumors relative to first-generation CAR-macrophages.

CAR-T细胞疗法已成功治疗血液恶性肿瘤。由于其免疫调节能力以及渗透实体肿瘤和吞噬肿瘤细胞的能力，巨噬细胞也引起了关注。第一代基于CD3ζ的CAR-巨噬细胞可以以抗原依赖的方式吞噬肿瘤细胞。在这项研究中，我们通过工程诱导多能干细胞衍生的巨噬细胞（iMACs），利用含有Toll样受体4细胞内Toll/IL-1R（TIR）结构域的CAR，显著增强了其抗肿瘤效果，相较于第一代CAR-巨噬细胞。此外，设计了串联的CD3ζ-TIR双信号CAR，赋予iMACs目标吞噬能力、抗原依赖的M1极化和NF-κB依赖的M2抵抗力，以及调节肿瘤微环境的能力。我们还勾勒了CAR诱导的巨噬细胞吞噬肿瘤细胞凋亡体的机制。综合而言，我们提供了一种第二代CAR-iMAC，具有正交吞噬和极化的能力，在治疗实体肿瘤方面相较于第一代CAR-巨噬细胞具有更卓越的抗肿瘤功能。

链接：

https://pan.baidu.com/s/15c7qssHdGeIh5a_SZeyXvA?pwd=3vjx

提取码：3vjx

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