Frontiers in immunology · 2025
Urokinase-type plasminogen activator deficiency enhances CD8+ T cell infiltration and anti-PD-1 therapy efficacy in prostate cancer.
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Li Xiaoyi, Zhang Xiao, Fu Xing, Wu Hong, Ye Xinyu, Huang Xin, Cui Yuhao, Qian Chao-Nan, Lu Yi, Zhang Jian
Аннотация
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.
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.