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 T 细胞与肿瘤细胞的相互作用，成为实体瘤中抗肿瘤免疫的屏障，因此需要阐明特定 ECM 蛋白影响实体瘤促纤维增生基质内 T 细胞运动和活性的机制。 。在这里，我们发现 VI 型胶原蛋白 (Col VI) 沉积与人类前列腺癌样本中的基质 T 细胞密度相关。此外，与纤连蛋白和 I 型胶原相比，CD4+ T 细胞在纯化的 Col VI 表面上的运动性被完全消除。重要的是，粘附到 Col VI 表面的 T 细胞显示出细胞扩散和纤维状肌动蛋白减少，表明牵引力产生减少，同时伴随着整合素β1聚集减少。我们发现，前列腺肿瘤微环境中 CD4+ T 细胞很大程度上缺乏整合素 α1 的表达，α1β1 整合素异二聚体的阻断抑制了 CD8+ T 细胞在前列腺成纤维细胞衍生基质上的运动，而 ITGA1 的重新表达则改善了运动。综上所述，我们发现前列腺癌中富含 Col VI 的微环境会降低缺乏整合素 α1 的 CD4+ T 细胞的运动性，导致它们在基质中积累，从而抑制抗肿瘤 T 细胞反应。