Enhancing antibody-dependent cellular phagocytosis by Re-education of tumor-associated macrophages with resiquimod-encapsulated liposomes
Enhancing antibody-dependent cellular phagocytosis by Re-education of tumor-associated macrophages with resiquimod-encapsulated liposomes
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DOI：
10.1016/j.biomaterials.2020.120601
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发表时间：
2021-01-01
期刊：
影响因子：
14
通讯作者：
Kuroda, Shun'ichi
中科院分区：
文献类型：
--
作者：
Li, Hao;Somiya, Masaharu;Kuroda, Shun'ichi
肿瘤相关巨噬细胞（TAM）存在于几乎所有肿瘤中，并形成肿瘤微环境的主要部分。TAM分为两类：抑瘤M1型和促瘤M2型。大多数TAM被肿瘤细胞训练成M2型，这支持肿瘤生长并使免疫治疗无效。抗体依赖性细胞吞噬作用（ADCP）是抗体治疗癌症的重要机制，而这一机制依赖于TAM。在这项研究中，我们发现M1型巨噬细胞比M2型巨噬细胞引起更有效的ADCP反应，这一点得到了三种肿瘤细胞系Raji、A431和SKBR 3的证实，沿着的分别是其相应的治疗性抗体利妥昔单抗、抗EGFR小鼠单克隆抗体（克隆528）和曲妥珠单抗。瑞喹莫特（Resiquimod，R848）是一种免疫系统激活剂，已被证明可以刺激M1型巨噬细胞，并将TAM从M2型再教育为M1型。通过用R848处理TAM，ADCP反应在体外和体内小鼠异种移植模型中显著增加。R848-LPs不仅在肿瘤组织中有效蓄积，而且在TAM中分布。R848-LP与抗EGFR小鼠单克隆抗体（克隆528）的协同作用显著抑制体内WiDr肿瘤生长。我们的研究还显示，R848的TAM靶向递送能够将TAM再教育为M1型，增强抗体的ADCP效应，并因此增强治疗性抗体的抗肿瘤效应。
Tumor-associated macrophages (TAMs) exist in nearly all tumors, and form a major part of the tumor micro environment. TAMs are divided into two groups: tumor-suppressing M1 type and tumor-promoting M2 type. Most TAMs are educated by the tumor cells to become M2 type, which support tumor growth and make immunotherapy ineffective. Antibody-dependent cellular phagocytosis (ADCP) is an important mechanism for antibody cancer therapy, and this mechanism is dependent on TAMs. In this study, we found that the M1 type macrophages elicit a more efficient ADCP response than the M2 type, which was confirmed by three tumor cell lines, Raji, A431, and SKBR3, along with their corresponding therapeutic antibody Rituximab, anti-EGFR mouse monoclonal antibody (clone 528), and Trastuzumab, respectively. Resiquimod (R848), an immune system activating agent, has been shown to stimulate the M1 type macrophages, and re-educate the TAMs from M2 type to M1 type. By treating TAMs with R848, the ADCP response increased significantly in vitro and in in vivo mouse xenograft models. R848 encapsulated liposomes (R848-LPs) not only accumulated efficiently in the tumor tissues, but also distributed in the TAMs. Synergizing the R848-LPs with the anti-EGFR mouse monoclonal antibody (clone 528) significantly inhibited WiDr-tumor growth in vivo. Our study also revealed that the TAM-targeted delivery of R848 is able to re-educate the TAMs to M1 type, enhance the ADCP effect of the antibodies, and hence, enhance the anti-tumor effect of the therapeutic antibodies.