Metastasis is the leading cause of cancer-related deaths. Recent developments in cancer immunotherapy have shown exciting therapeutic promise for metastatic patients. While most therapies target T cells, other immune cells, such as monocytes, hold great promise for therapeutic intervention. In our study, we provide primary evidence of direct engagement between human monocytes and tumor cells in a 3D vascularized microfluidic model. We first characterize the novel application of our model to investigate and visualize at high resolution the evolution of monocytes as they migrate from the intravascular to the extravascular micro-environment. We also demonstrate their differentiation into macrophages in our all-human model. Our model replicates physiological differences between different monocyte subsets. In particular, we report that inflammatory, but not patrolling, monocytes rely on actomyosin based motility. Finally, we exploit this platform to study the effect of monocytes, at different stages of their life cycle, on cancer cell extravasation. Our data demonstrates that monocytes can directly reduce cancer cell extravasation in a non-contact dependent manner. In contrast, we see little effect of monocytes on cancer cell extravasation once monocytes transmigrate through the vasculature and are macrophage-like. Taken together, our study brings novel insight into the role of monocytes in cancer cell extravasation, which is an important step in the metastatic cascade. These findings establish our microfluidic platform as a powerful tool to investigate the characteristics and function of monocytes and monocyte-derived macrophages in normal and diseased states. We propose that monocyte-cancer cell interactions could be targeted to potentiate the anti-metastatic effect we observe in vitro, possibly expanding the milieu of immunotherapies available to tame metastasis.

中文翻译：

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在3D血管化微流模型中，单核细胞对肿瘤细胞外渗的影响。

转移是癌症相关死亡的主要原因。癌症免疫疗法的最新发展已显示出对转移性患者的令人兴奋的治疗前景。尽管大多数疗法都针对T细胞，但其他免疫细胞（例如单核细胞）仍有望用于治疗。在我们的研究中，我们提供了人类单核细胞与肿瘤细胞在3D血管化微流模型中的直接结合的主要证据。我们首先表征模型的新颖应用，以高分辨率调查和可视化单核细胞从血管内迁移到血管外微环境的演变。在我们的全人类模型中，我们还展示了它们分化为巨噬细胞的能力。我们的模型复制了不同单核细胞亚群之间的生理差异。特别是，我们报告说，但不巡逻，单核细胞依靠肌动球蛋白为基础的运动。最后，我们利用该平台研究单核细胞在其生命周期的不同阶段对癌细胞外渗的影响。我们的数据表明，单核细胞可以以非接触依赖的方式直接减少癌细胞的外渗。相反，一旦单核细胞通过脉管系统迁移并呈巨噬细胞样，我们就看不到单核细胞对癌细胞外渗的影响。综上所述，我们的研究为单核细胞在癌细胞外渗中的作用带来了新的见解，这是转移级联中的重要一步。这些发现建立了我们的微流体平台，成为研究正常和患病状态下单核细胞和源自单核细胞的巨噬细胞的特征和功能的有力工具。