PO.IM01.15 · 免疫学
治疗性抗体在免疫抑制性肿瘤微环境的先进体外模型中抑制靶点介导的免疫迁移
Therapeutic antibody inhibits target-mediated immune migration in advanced in-vitromodelofanimmune suppressive tumormicroenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
越来越明确的是，当前的免疫肿瘤学治疗在不损伤周围组织的情况下产生足够的靶向治疗效果方面存在不足。免疫抑制性肿瘤微环境近来已成为一种新的治疗靶点，因为它驱动肿瘤生长、治疗耐药和转移，而不再仅仅聚焦于肿瘤本身作为主要靶点。然而，当前的体外系统往往无法复现肿瘤微环境，从而阻碍了准确的疗效评估。本研究使用免疫抑制性肿瘤微环境的先进体外模型来研究治疗性抗体的治疗效果。在此，我们报告使用基于器官芯片的模型，在一类被称为血管周巨噬细胞（PVM）的免疫抑制性巨噬细胞亚群背景下研究免疫细胞迁移，以及研究这些细胞释放的一种靶蛋白。该模型包含内皮血管（HUVEC）、巨噬细胞（PVM或M1）和免疫细胞（PBMCs或T细胞），用于研究这些细胞之间的相互作用，并确定靶蛋白和抗体的效应。免疫细胞迁移的水平显示依赖于免疫细胞的激活状态和内皮的预处理。PVMs显示对免疫细胞迁移具有抑制作用，与之相反，M1巨噬细胞增加了迁移免疫细胞的数量。所释放的靶蛋白被发现可减少T细胞迁移，尤其是针对受刺激的T细胞。最后，在加入靶蛋白后对新型治疗性抗体进行了评估。对于其中一种抗体，观察到受刺激T细胞迁移增加。这些发现突显了靶向PVMs及其释放蛋白作为免疫抑制性微环境重要组成部分的潜力。此外，本研究显示了该先进体外模型在评估治疗性抗体方面的实用性。未来，该系统将用于在免疫抑制性肿瘤微环境背景下测试更多的治疗药物。
查看英文原文 English abstract
It has become increasingly clear that current immune-oncology treatments are inadequate in generating sufficient targeted treatment effects without damaging the surrounding tissue. Rather than focusing on the tumor as the main target, the immune suppressive tumor microenvironment has recently become a novel therapeutic target as it drives tumor growth, therapy resistance and metastasis. However, current in vitro systems often fail to replicate the tumor microenvironment hindering accurate efficacy evaluation. This study used an advanced in-vitro model of an immune suppressive tumor microenvironment to study treatment effects of therapeutic antibodies. Here we report on the use of an organ-on-a-chip based model to study immune cell migration in the context of a subset of immune suppressive macrophages, known as perivascular macrophages (PVM), and on a target protein released by these cells. The model contains an endothelial vessel (HUVEC), macrophages (PVM or M1) and immune cells (PBMCs or T cells) to study the interaction between these cells and determine the effect of target protein and antibodies. The level of immune cell migration showed to be dependent on the activation state of immune cells and pretreatment of the endothelium. PVMs shown to have an inhibitory effect on immune cells migration, in contrast to M1 macrophages that increased the number of migrated immune cells. The released target protein was found to reduce T cell migration, specifically for stimulated T cells. Finally, novel therapeutic antibodies were assessed after addition of the target protein. For one of the antibodies increased migration of stimulated T cells was observed. These findings highlight the potential of targeting PVMs and their released proteins, as important elements of an immune suppressive microenvironment. Additionally, the study shows the utility of the advanced in-vitro model for evaluating therapeutic antibodies. In the future the system will be used for testing additional therapeutics in the context of an immune suppressive tumor microenvironment.
利益披露 Disclosure
W. Strijker,
MIMETAS B.V Employment.
I. Voskamp,
MIMETAS B.V Employment.
B. Duggan,
MIMETAS B.V Employment.
R. Van Vught,
MIMETAS B.V Employment.
L. de Haan,
MIMETAS B.V Employment.
W. Celus,
Montis Biosciences Employment.
L. Gijzen,
MIMETAS B.V Employment.