Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, #81 Meishan Road, Shushan District, Hefei, China.
Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Shushan District, Hefei, China.
J Transl Med. 2023 Sep 22;21(1):654. doi: 10.1186/s12967-023-04479-8.
The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer.
In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M.
We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8 cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8 T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression.
We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.
嵌合抗原受体 (CAR)-T 疗法对实体瘤的治疗效果有限，这是由于 CAR-T 细胞向实体瘤的浸润有限，以及免疫抑制性肿瘤微环境使 CAR-T 细胞失活。巨噬细胞是固有和适应性免疫的重要组成部分，其独特的吞噬功能已被探索用于构建针对实体瘤的 CAR 巨噬细胞 (CAR-M)。本研究旨在探讨 CAR-M 在卵巢癌中的治疗应用。
在本研究中，我们构建了新型的 CAR 结构，由人源化抗 HER2 或 CD47 scFv、CD8 铰链区和跨膜区以及 4-1BB 和 CD3ζ 细胞内区组成。我们检查了卵巢癌细胞上 HER2 CAR-M 和 CD47 CAR-M 的吞噬作用以及对适应性免疫的促进作用。使用两个同种异体肿瘤模型来评估 HER2 CAR-M 和 CD47 CAR-M 的体内抗肿瘤活性。
我们构建了针对 HER2 和 CD47 的 CAR-M，并验证了它们在体内和体外对卵巢癌细胞的吞噬能力。构建的 CAR-M 表现出对卵巢癌细胞的抗原特异性吞噬作用，并能激活 CD8 细胞毒性 T 淋巴细胞 (CTL) 分泌各种抗肿瘤因子。在体内模型中，使用了具有人类样免疫系统的小鼠。我们发现 CAR-M 增强了 CD8 T 细胞的激活，影响了肿瘤相关巨噬细胞 (TAM) 的表型，并导致肿瘤消退。
我们证明了我们构建的新型 HER2 CAR-M 和 CD47 CAR-M 对体外和体内靶抗原阳性卵巢癌的抑制作用，并初步验证这种抑制作用是由于吞噬作用、促进适应性免疫和对肿瘤微环境的影响。
