A new strategy for cancer immunotherapy using dendritic cell-macrophage hybrids

使用树突状细胞-巨噬细胞杂交体进行癌症免疫治疗的新策略

基本信息

批准号：
16390313
负责人：
MATSUE Hiroyuki
金额：
$ 9.15万
依托单位：
University of Yamanashi
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390313/
关键词：
Dendritic cells Macrophage Cell fusion Hybrid cells Tumor immunity Immunotherapy Gap junction Connexin ハイブリド細胞癌免疫療法

项目摘要

Dendritic cells (DC) are special subsets of antigen presenting cells (APC) characterized by their strong abilities to induce acquired immunity including anti-tumor immunity and by their weak abilities to directly (i.e., cytotoxic capability) and/or indirectly (via ADCC) kill harmful cells (e.g., tumor cells). Conversely, macrophages (mΦ) serve as weak APC and cells possessing ADCC. Our hypothesis was that DC-mΦ hybrids may overcome each weakness and exert beneficial and strong anti-tumor immunity. To test this hypothesis, we first established a new strategy to select only hybrid cells by our double-selection method. Second, using this selection method, we fused DC and mΦ, and then established hybrids were examined for their phenotypes. We found difficulties to distinguish these two cell types by functional and surface phenotypes and also found heterogeneity between hybrid clones (Matsue H, et al., Cancer Biology & Therapy, 3:1145-1151, 2004). During a series of hybrid experiments, we r … More ealized that DC were activated by cell fusion at extremely high cell density. We shifted our research focus to figure out the reason for their activation and found that DC are activated via gap junctions during cell fusion. As a by-product of this project, we discovered that gap junction-mediated intercellular communication (GJIC) between DC is required for effective activation of DC. (Matsue H, et al., J Immunol. 176:181-190, 2006). We believe that harness of GJIC between DC may become a new strategy to induce or silence the immunity for new therapeutic modalities.In summary, although we failed to develop a new strategy for anti-cancer therapy using DC-mΦ hybrids, our fusion method formed the technical basis for generation of artificial new immune cells that have two totally different immunological functions. This strategy will provide a new avenue for cell-based immunotherapies. In addition, pharmacological manipulation of GJIC will provide another direction of DC research to control the immunity. Less

树突状细胞 (DC) 是抗原呈递细胞 (APC) 的特殊亚群，其特征是诱导获得性免疫（包括抗肿瘤免疫）的能力很强，但直接（即细胞毒性能力）和/或间接（通过 ADCC）的能力较弱离线杀死有害细胞（例如肿瘤细胞），巨噬细胞（mΦ）充当弱 APC 和具有 ADCC 的细胞，我们的假设是 DC-mΦ 杂交体可以克服每个弱点并发挥有益和强大的作用。为了检验这一假设，我们首先建立了一种新策略，通过双重选择方法仅选择杂交细胞，然后，使用这种选择方法，我们融合 DC 和 mΦ，然后检查建立的杂交细胞的表型。我们发现很难通过功能和表面表型来区分这两种细胞类型，并且还发现杂交克隆之间的异质性（Matsue H 等人，Cancer Biology & Therapy，3：1145-1151，2004）。在一系列混合实验中，我们意识到 DC 在极高的细胞密度下被细胞融合激活。我们将研究重点转向找出其激活的原因，并发现 DC 在细胞融合过程中通过间隙连接被激活。作为该项目的副产品，我们发现 DC 之间的间隙连接介导的细胞间通讯 (GJIC) 是有效激活 DC 所必需的（Matsue H 等人，《免疫学杂志》，2017 年）。 176:181-190, 2006）我们相信，利用 DC 之间的 GJIC 可能成为诱导或沉默免疫的新策略，以实现新的治疗方式。总而言之，尽管我们未能开发出一种新的抗癌治疗策略。 DC-mΦ杂交，我们的融合方法形成了产生具有两种完全不同的免疫功能的人工新免疫细胞的技术基础，该策略将为基于细胞的免疫疗法提供新的途径。此外，GJIC的药理操作将为DC研究提供另一个方向来控制免疫。