研究发现肿瘤中纤溶酶原激活剂抑制剂-1 (PAI-1) 水平升高与癌症患者不良的临床结果相关。尽管大量数据支持 PAI-1 参与癌症进展，但 PAI-1 是否有助于肿瘤免疫监视仍不清楚。本研究的目的是确定PAI-1是否通过调节免疫检查点分子的表达来抑制对癌症的免疫反应，并证明PAI-1抑制在癌症治疗中的潜力。PAI-1对免疫检查点分子表达的影响在几种人类和小鼠肿瘤细胞系中研究了免疫检查点分子程序性细胞死亡配体 1 (PD-L1)。此外，我们还培育了荷瘤小鼠，并评估了 PAI-1 抑制剂对肿瘤进展或对参与肿瘤免疫的细胞的肿瘤浸润的影响，无论是单独使用还是与免疫检查点抑制剂联合使用。PAI-1 诱导 PD-L1通过 JAK/STAT 信号通路在几种类型的肿瘤细胞和周围细胞中表达。阻断 PAI-1 会阻碍肿瘤细胞中 PD-L1 的诱导，从而显着减少肿瘤部位免疫抑制细胞的丰度并增加细胞毒性 T 细胞浸润，最终导致肿瘤消退。 PAI-1 抑制剂引起的抗肿瘤作用在免疫缺陷小鼠中消失，表明 PAI-1 阻断通过刺激免疫系统诱导肿瘤消退。此外，将 PAI-1 抑制剂与免疫检查点抑制剂相结合可显着促进肿瘤消退。PAI-1 通过增加 PD-L1 表达来保护肿瘤免受免疫监视；因此，治疗性 PAI-1 阻断可能对治疗恶性肿瘤有价值。版权所有 © 2024 Ibrahim、Fujimura、Uno、Terada、Hirano、Hosokawa、Ohta、Miyata、Ando 和 Yahata。

Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy.The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors.PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression.PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.Copyright © 2024 Ibrahim, Fujimura, Uno, Terada, Hirano, Hosokawa, Ohta, Miyata, Ando and Yahata.