Abstract

The prostate tumor microenvironment (TME) is strongly immunosuppressive; it is largely driven by alteration in cell phenotypes (i.e. tumor-associated macrophages and exhausted cytotoxic T cells) that result in pro-tumorigenic conditions and tumor growth. A greater understanding into how these altered immune cell phenotypes are developed and could potentially be reversed would provide important insights into improved treatment efficacy for prostate cancer. Here, we report a microfluidic model of the prostate TME that mimics prostate ducts across various stages of prostate cancer progression, with associated stroma and immune cells. Using this platform, we exposed immune cells to a benign prostate TME or a metastatic prostate TME and investigated their metabolism, gene and cytokine expression. Immune cells exposed to the metastatic TME showed metabolic differences with a higher redox ratio indicating a switch to a more glycolytic metabolic profile. These cells also increased expression of pro-tumor response cytokines that have been shown to increase cell migration and angiogenesis such as Interleukin-1 (IL-1) a and Granulocyte-macrophage colony-stimulating factor (GM-CSF). Lastly, we observed decreased TLR, STAT signaling and TRAIL expression, suggesting that phenotypes derived from exposure to the metastatic TME could have an impaired anti-tumor response. This platform could provide a valuable tool for studying immune cell phenotypes in in vitro tumor microenvironments.

中文翻译：

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用于研究肿瘤微环境诱导的免疫细胞激活的生物工程器官型前列腺模型

摘要

前列腺肿瘤微环境 (TME) 具有强烈的免疫抑制作用；它主要是由细胞表型（即肿瘤相关巨噬细胞和耗尽的细胞毒性 T 细胞）的改变驱动的，这些改变导致促肿瘤发生条件和肿瘤生长。更深入地了解这些改变的免疫细胞表型是如何形成的，以及如何可能被逆转，将为提高前列腺癌的治疗效果提供重要的见解。在这里，我们报告了一种前列腺 TME 的微流体模型，该模型模拟了前列腺癌进展各个阶段的前列腺导管，以及相关的基质和免疫细胞。使用这个平台，我们将免疫细胞暴露于良性前列腺 TME 或转移性前列腺 TME，并研究它们的代谢、基因和细胞因子表达。暴露于转移性 TME 的免疫细胞显示出代谢差异，较高的氧化还原率表明转变为糖酵解代谢模式。这些细胞还增加了促肿瘤反应细胞因子的表达，这些细胞因子已被证明可以增加细胞迁移和血管生成，例如白细胞介素 1 (IL-1)a和粒细胞-巨噬细胞集落刺激因子 (GM-CSF)。最后，我们观察到 TLR、STAT 信号和 TRAIL 表达减少，表明暴露于转移性 TME 的表型可能具有受损的抗肿瘤反应。该平台可为研究体外肿瘤微环境中的免疫细胞表型提供有价值的工具。