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<p>Glioblastoma (GBM) cells mediate immunosuppressive microenvironment, leading to poor response to programmed death-ligand 1(PD-L1) inhibitor therapy. How PD-L1 in GBM cells confers to GBM immunosuppressive microenvironment remains unclear. Here, we demonstrate that PD-L1 activated GP130/JAK2/STAT3/IRAK2/NFκB/IL6 pathway. We showed that PD-L1 was elevated in human primary GBM and promoted GBM cell viability, migration and invasion via activating janus kinase 2(JAK2) by interacting with glycoprotein 130(GP130) and PD-1 in GBM cells, leading to the activation of signal transducer and activator of transcription 3 (STAT3), a master that renders GBM immunosuppression. Overexpressing STAT3 reversed the effect of silencing PD-L1-mediated cell viability, proliferation, migration and invasion. STAT3 promoted interleukin-1 receptor-associated kinase 2(IRAK2) transcription. IRAK2 overexpression rescued the effect of silencing STAT3-mediated cell viability, proliferation, migration and invasion. Additionally, IRAK2 facilitated interleukin-6 (IL6) expression via activating nuclear factor kappa-B (NFκB). Our results indicate that PD-L1/GP130/JAK2/STAT3/IRAK2/NFκB/IL6 axis promotes GBM cell viability, proliferation, migration and invasion via interacting with GP130 and PD-1 in GBM cells. Additionally, STAT3 transcriptionally promoted PD-L1 expression, thus forming loops to lead to PD-L1 autoregulation. IL6 positively correlated with GBM-associated macrophages, myeloid-derived suppressor cells and the inhibition of dendritic cells. Our study suggests that PD-L1 autoregulation may create immunosuppressive GBM via activating GP130/JAK2/STAT3/IRAK2/IL-6 pathway.</p>

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PD-L1 autoregulation promotes the proliferation, migration and invasion of glioblastoma cells via GP130/JAK2/STAT3/IRAK2/IL6 signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • Xin Xie,
  • Jingdi Bai,
  • Yuhui Peng,
  • Pingping Chen,
  • Zhuxue Zhang,
  • Daogui Fan,
  • Feng Zhou,
  • Yuan Yuan,
  • Jiyun Liu,
  • Yu Zhou,
  • Qin Hong,
  • Jianjun Hu,
  • Juanjuan Duan,
  • Wenli Fu,
  • Ting Zhang,
  • Hongmei Zeng,
  • Jie Deng,
  • Yangting Dong,
  • Ying Liu,
  • Xiaolan Qi,
  • Wei Hong,
  • Yan He,
  • Chunlin Zhang,
  • Wenfeng Yu,
  • Qintian Yang,
  • Wei Yi,
  • Hua Bai,
  • Qifang Zhang

摘要

Glioblastoma (GBM) cells mediate immunosuppressive microenvironment, leading to poor response to programmed death-ligand 1(PD-L1) inhibitor therapy. How PD-L1 in GBM cells confers to GBM immunosuppressive microenvironment remains unclear. Here, we demonstrate that PD-L1 activated GP130/JAK2/STAT3/IRAK2/NFκB/IL6 pathway. We showed that PD-L1 was elevated in human primary GBM and promoted GBM cell viability, migration and invasion via activating janus kinase 2(JAK2) by interacting with glycoprotein 130(GP130) and PD-1 in GBM cells, leading to the activation of signal transducer and activator of transcription 3 (STAT3), a master that renders GBM immunosuppression. Overexpressing STAT3 reversed the effect of silencing PD-L1-mediated cell viability, proliferation, migration and invasion. STAT3 promoted interleukin-1 receptor-associated kinase 2(IRAK2) transcription. IRAK2 overexpression rescued the effect of silencing STAT3-mediated cell viability, proliferation, migration and invasion. Additionally, IRAK2 facilitated interleukin-6 (IL6) expression via activating nuclear factor kappa-B (NFκB). Our results indicate that PD-L1/GP130/JAK2/STAT3/IRAK2/NFκB/IL6 axis promotes GBM cell viability, proliferation, migration and invasion via interacting with GP130 and PD-1 in GBM cells. Additionally, STAT3 transcriptionally promoted PD-L1 expression, thus forming loops to lead to PD-L1 autoregulation. IL6 positively correlated with GBM-associated macrophages, myeloid-derived suppressor cells and the inhibition of dendritic cells. Our study suggests that PD-L1 autoregulation may create immunosuppressive GBM via activating GP130/JAK2/STAT3/IRAK2/IL-6 pathway.