Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
Division of Biosignal Regulation, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
Front Immunol. 2023 Dec 14;14:1294814. doi: 10.3389/fimmu.2023.1294814. eCollection 2023.
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs , we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34 hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)- and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs.
肿瘤相关巨噬细胞（TAMs）在肿瘤微环境中大量存在，被认为是癌症免疫治疗的潜在靶点。为了研究靶向人 TAMs 的药物的抗肿瘤作用，我们在此建立了基于免疫缺陷小鼠的临床前肿瘤异种移植模型，这些小鼠表达多种人细胞因子，并通过人 CD34 造血干细胞和祖细胞（HIS-MITRG 小鼠）的移植重建了人的免疫系统。HIS-MITRG 小鼠支持人细胞系（Raji）和患者来源的 B 细胞淋巴瘤的生长，以及人巨噬细胞浸润到其肿瘤中。我们研究了一种针对人 SIRPα（SE12C3）的抗体的潜在抗肿瘤作用，该抗体抑制肿瘤细胞上的 CD47 与人类巨噬细胞上的 SIRPα 的相互作用，从而促进 Fcγ 受体介导的前者细胞被后者吞噬。与利妥昔单抗（抗人 CD20 抗体）联合使用 SE12C3 可显著抑制 Raji 肿瘤在 HIS-MITRG 小鼠中的生长，而单独使用利妥昔单抗则没有。这种增强的抗肿瘤作用依赖于人巨噬细胞，并且归因于人巨噬细胞对淋巴瘤细胞的利妥昔单抗依赖性吞噬作用增强。用利妥昔单抗和 SE12C3 治疗还诱导人 TAMs 向促炎表型重编程。此外，联合治疗基本上可以防止患者来源的弥漫性大 B 细胞淋巴瘤在 HIS-MITRG 小鼠中的生长。因此，我们的研究结果支持将 HIS-MITRG 小鼠作为模型用于评估潜在治疗剂（例如针对人 SIRPα 的抗体）的临床前评估，这些治疗剂靶向人 TAMs。
