Roberts LaDeidra Monét, Perez Matthew J, Balogh Kristen N, Mingledorff Garnett, Cross Janet V, Munson Jennifer M
Department of Biomedical Engineering and Mechanics, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA 24016, USA.
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USA.
Cancers (Basel). 2022 Jun 18;14(12):3008. doi: 10.3390/cancers14123008.
At the site of the tumor, myeloid derived suppressor cells (MDSCs) infiltrate and interact with elements of the tumor microenvironment in complex ways. Within the invading tumor, MDSCs are exposed to interstitial fluid flow (IFF) that exists within the chronic inflammatory tumor microenvironment at the tumor-lymphatic interface. As drivers of cell migration and invasion, the link between interstitial fluid flow, lymphatics, and MDSCs have not been clearly established. Here, we hypothesized that interstitial fluid flow and cells within the breast tumor microenvironment modulate migration of MDSCs. We developed a novel 3D model to mimic the breast tumor microenvironment and incorporated MDSCs harvested from 4T1-tumor bearing mice. Using live imaging, we found that sorted GR1+ splenocytes had reduced chemotactic index compared to the unsorted population, but their speed and displacement were similar. Using our adapted tissue culture insert assay, we show that interstitial fluid flow promotes MDSC invasion, regardless of absence or presence of tumor cells. Coordinating with lymphatic endothelial cells, interstitial fluid flow further enhanced invasion of MDSCs in the presence of 4T1 cells. We also show that VEGFR3 inhibition reduced both MDSC and 4T1 flow response. Together, these findings indicate a key role of interstitial fluid flow in MDSC migration as well as describe a tool to explore the immune microenvironment in breast cancer.
在肿瘤部位，髓源性抑制细胞（MDSCs）浸润并以复杂的方式与肿瘤微环境的成分相互作用。在侵袭性肿瘤中，MDSCs暴露于肿瘤-淋巴界面处慢性炎症肿瘤微环境中存在的间质液流动（IFF）。作为细胞迁移和侵袭的驱动因素，间质液流动、淋巴管和MDSCs之间的联系尚未明确建立。在此，我们假设间质液流动和乳腺肿瘤微环境中的细胞调节MDSCs的迁移。我们开发了一种新型三维模型来模拟乳腺肿瘤微环境，并纳入了从携带4T1肿瘤的小鼠中收获的MDSCs。通过实时成像，我们发现与未分选的群体相比，分选的GR1+脾细胞趋化指数降低，但其速度和位移相似。使用我们改进的组织培养插入物试验，我们表明，无论是否存在肿瘤细胞，间质液流动都能促进MDSC的侵袭。与淋巴管内皮细胞协同作用，间质液流动在存在4T1细胞的情况下进一步增强了MDSCs的侵袭。我们还表明，VEGFR3抑制降低了MDSC和4T1的流动反应。总之，这些发现表明间质液流动在MDSC迁移中起关键作用，并描述了一种探索乳腺癌免疫微环境的工具。
