肿瘤细胞治疗研究
英文原题：Urokinase-type plasminogen activator deficiency enhances CD8(+) T cell infiltration and anti-PD-1 therapy efficacy in prostate cancer.
uPA是前列腺癌中重要的免疫抑制调节因子。抑制uPA可增强CD8⁺ T细胞功能，并与免疫检查点阻断产生协同作用，支持将uPA靶向作为一种提高前列腺癌免疫治疗疗效的新策略。
尿激酶型纤溶酶原激活物（uPA）在前列腺癌中表达上调，但其对免疫微环境的全面影响及潜在机制尚未完全阐明。
uPA 表达在临床前列腺癌标本中进行分析，并与 CD8⁺ T 细胞浸润相关联。在 uPA 缺陷（uPA -/-）和 uPA 抑制剂 UK122 处理的小鼠模型中评估肿瘤生长。通过 CyTOF 和流式细胞术评估免疫浸润。测试抗 CD19 嵌合抗原受体（CAR）工程化的 WT 或 uPA -/- CD8⁺ T 细胞对 RM1-CD19 细胞的细胞毒性。评估 UK122 与抗 PD-1 治疗的联合应用。
前列腺癌标本中uPA升高与CD8⁺ T细胞浸润呈负相关。uPA基因敲除和UK122均通过增强抗肿瘤免疫显著减弱肿瘤生长。uPA缺失显著增加CD8⁺ T细胞浸润。与WT CD8⁺ T细胞相比，uPA -/- CD8⁺ T细胞表现出增强的细胞毒性。肿瘤浸润性uPA -/- CD8⁺ T细胞显示更高的PD-1表达。UK122与抗PD-1治疗协同促进肿瘤消退。
INTRODUCTION: Urokinase-type plasminogen activator (uPA) is upregulated in prostate cancer, but its comprehensive impact on the immune microenvironment and the underlying mechanisms remains to be fully elucidated. METHODS: uPA expression was analyzed in clinical prostate cancer specimens and correlated with CD8⁺ T cell infiltration. Tumor growth was assessed in the uPA-deficient (uPA -/- )and the uPA inhibitor UK122-treated mouse model. Immune infiltration was evaluated by CyTOF and flow cytometry. Anti-CD19 chimeric antigen receptor (CAR)-engineered WT or uPA -/- CD8⁺ T cells were tested for cytotoxicity against RM1-CD19 cells. The combination of UK122 and anti-PD-1 therapy was assessed. RESULTS: Elevated uPA in prostate cancer specimens inversely correlated with CD8⁺ T cell infiltration. Both genetic uPA ablation and UK122 significantly attenuated tumor growth by enhancing antitumor immunity. uPA deficiency markedly increased CD8⁺ T cell infiltration. uPA -/- CD8⁺ T cells exhibited enhanced cytotoxicity compared to WT CD8⁺ T cells. Tumor-infiltrating uPA -/- CD8⁺ T cells showed higher PD-1 expression. UK122 synergized with anti-PD-1 therapy to promote tumor regression. DISCUSSION: uPA is a significant immunosuppressive regulator in prostate cancer. Its inhibition enhances CD8⁺ T cell function and synergizes with immune checkpoint blockade, supporting uPA targeting as a novel strategy to improve prostate cancer immunotherapy efficacy.
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