Institute for NanoBioTechnology, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA.
Matrix Biol. 2023 Aug;121:90-104. doi: 10.1016/j.matbio.2023.06.002. Epub 2023 Jun 16.
The tumor extracellular matrix (ECM) is a barrier to anti-tumor immunity in solid tumors by disrupting T cell-tumor cell interaction underlying the need for elucidating mechanisms by which specific ECM proteins impact T cell motility and activity within the desmoplastic stroma of solid tumors. Here, we show that Collagen VI (Col VI) deposition correlates with stromal T cell density in human prostate cancer specimens. Furthermore, motility of CD4+ T cells is completely ablated on purified Col VI surfaces when compared with Fibronectin and Collagen I. Importantly, T cells adhered to Col VI surfaces displayed reduced cell spreading and fibrillar actin, indicating a reduction in traction force generation accompanied by a decrease in integrin β1 clustering. We found that CD4+ T cells largely lack expression of integrin α1 in the prostate tumor microenvironment and that blockade of α1β1 integrin heterodimers inhibited CD8+ T cell motility on prostate fibroblast-derived matrix, while re-expression of ITGA1 improved motility. Taken together, we show that the Col VI-rich microenvironment in prostate cancer reduces the motility of CD4+ T cells lacking integrin α1, leading to their accumulation in the stroma, thus putatively inhibiting anti-tumor T cell responses.
肿瘤细胞外基质（ECM）通过破坏肿瘤细胞与 T 细胞的相互作用，成为实体瘤中抗肿瘤免疫的障碍，这就需要阐明特定 ECM 蛋白如何影响 T 细胞在实体瘤纤维母细胞基质中的迁移和活性。在这里，我们发现胶原 VI（Col VI）的沉积与人前列腺癌标本中的基质 T 细胞密度相关。此外，与纤连蛋白和胶原 I 相比，CD4+T 细胞在纯化的 Col VI 表面上的迁移能力完全被阻断。重要的是，与 Col VI 表面黏附的 T 细胞显示出细胞铺展和纤维状肌动蛋白减少，表明牵引力生成减少，同时整合素 β1 聚类减少。我们发现，在前列腺肿瘤微环境中，CD4+T 细胞基本上缺乏整合素 α1 的表达，并且阻断 α1β1 整合素异二聚体抑制了 CD8+T 细胞在前列腺成纤维细胞衍生基质上的迁移，而 ITGA1 的重新表达则改善了迁移。综上所述，我们表明，前列腺癌中富含 Col VI 的微环境降低了缺乏整合素 α1 的 CD4+T 细胞的迁移能力，导致它们在基质中积累，从而可能抑制抗肿瘤 T 细胞反应。
