Immunotherapies have not yielded significant clinical benefits for pancreatic ductal adenocarcinoma (PDA) because of the existence of an immunosuppressive tumour microenvironment (TME) characterized by a desmoplastic stroma containing infiltrated immune cells and activated pancreatic stellate cells (PSCs). This study aims to investigate the involvement of PAK1 in anti-tumour immunity. In PDA patients, low PAK1 expression, low activation of PSC and high CD8+ T cell/PAK1 ratios correlated with longer overall survival. In a murine PDA model, PAK1 knockout increased intra-tumoral CD4+ and CD8+ T cells, inhibited PSCs activation and extended survival. Inhibition of PAK1 reduced PSC-stimulated PDA cell proliferation and migration, blocked PSC-mediated protection of PDA cells from killing by cytotoxic lymphocytes and decreased intrinsic and PSC-stimulated PD-L1 expression in PDA cells, which further sensitized PDA cells to cytotoxic lymphocytes. Inhibition of PAK1 stimulates anti-tumour immunity by increasing intra-tumoral CD4+ and CD8+ T cells, and by sensitizing PDA cells to killing by cytotoxic lymphocytes via down-regulation of intrinsic and PSC-stimulated PD-L1 expression. PAK1 inhibitors, especially in combination with immune checkpoint inhibitors may result in improved efficacy of immunotherapy of PDA.

中文翻译：

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抑制PAK1通过下调PD-L1刺激抗肿瘤免疫力来抑制胰腺癌。

免疫疗法未对胰腺导管腺癌（PDA）产生明显的临床益处，因为存在一种免疫抑制性肿瘤微环境（TME），其特征为具有浸润性免疫细胞和活化的胰腺星状细胞（PSC）的增生基质。这项研究旨在调查PAK1在抗肿瘤免疫中的作用。在PDA患者中，低PAK1表达，低PSC活化和高CD8 + T细胞/ PAK1比值与更长的总生存期相关。在鼠PDA模型中，PAK1敲除增加了肿瘤内CD4 +和CD8 + T细胞，抑制了PSC的活化并延长了生存期。抑制PAK1可减少PSC刺激的PDA细胞的增殖和迁移，阻断PSC介导的PDA细胞免受细胞毒性淋巴细胞杀伤的保护，并降低PDA细胞中固有的和PSC刺激的PD-L1表达，这进一步使PDA细胞对细胞毒性淋巴细胞敏感。抑制PAK1通过增加肿瘤内CD4 +和CD8 + T细胞，以及通过下调内在和PSC刺激的PD-L1表达，使PDA细胞对细胞毒性淋巴细胞的杀伤作用而刺激抗肿瘤免疫力。PAK1抑制剂，尤其是与免疫检查点抑制剂联合使用，可能会提高PDA免疫疗法的疗效。通过下调内在和PSC刺激的PD-L1表达，使PDA细胞对细胞毒性淋巴细胞的杀伤敏感。PAK1抑制剂，尤其是与免疫检查点抑制剂联合使用，可能会提高PDA免疫疗法的疗效。通过下调内在和PSC刺激的PD-L1表达，使PDA细胞对细胞毒性淋巴细胞的杀伤敏感。PAK1抑制剂，尤其是与免疫检查点抑制剂联合使用，可能会提高PDA免疫疗法的疗效。