PD-L1 autoregulation promotes the proliferation, migration and invasion of glioblastoma cells via GP130/JAK2/STAT3/IRAK2/IL6 signaling pathway
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.
Authors
- Hongmei Zeng (ORCID: https://orcid.org/0000-0003-3999-3081)
- Daogui Fan
- Yang‐Ting Dong
- Jie Deng (ORCID: https://orcid.org/0000-0002-8883-8179)
- Yu‐Hui Peng (ORCID: https://orcid.org/0000-0002-1866-4679)
- Feng Zhou (ORCID: https://orcid.org/0000-0002-2402-4774)
- Qifang Zhang (ORCID: https://orcid.org/0000-0002-8264-0639)
- Xiaolan Qi (ORCID: https://orcid.org/0000-0002-9108-6772)
- Chunlin Zhang (ORCID: https://orcid.org/0000-0003-3957-8603)
- Ying Liu (ORCID: https://orcid.org/0000-0003-1699-9309)
- Zhuxue Zhang (ORCID: https://orcid.org/0000-0001-6899-7095)
- Jiyun Liu (ORCID: https://orcid.org/0000-0002-5352-5199)
- Juanjuan Duan
- Jianjun Hu (ORCID: https://orcid.org/0000-0003-2396-5983)
- Yu Zhou (ORCID: https://orcid.org/0000-0003-0457-221X)
- Yi Wei (ORCID: https://orcid.org/0000-0003-0943-7244)
- Pingping Chen (ORCID: https://orcid.org/0000-0002-2848-2465)
- Yan He (ORCID: https://orcid.org/0000-0003-0307-2651)
- Wenfeng Yu
- Xin Xie (ORCID: https://orcid.org/0000-0002-0945-969X)
- Hua Bai (ORCID: https://orcid.org/0000-0003-0348-7136)
- Qingzhu Yang (ORCID: https://orcid.org/0000-0002-3117-6573)
- Hong Qin (ORCID: https://orcid.org/0000-0003-0693-6865)
- Wenli Fu
- Yuan Yuan (ORCID: https://orcid.org/0000-0001-7440-8939)
- Wei Hong
- Jingdi Bai
- Ting Zhang (ORCID: https://orcid.org/0009-0008-5670-9955)
Institutions
- Guiyang Medical University (CN)
- Guizhou University (CN)
- Guizhou Cancer Hospital (CN)
- Affiliated Hospital of Guizhou Medical University (CN)
- Second Hospital of Tianjin Medical University (CN)
- The First People's Hospital of Guiyang (CN)
- Chongqing Jiulongpo People's Hospital (CN)
- Guizhou Provincial People's Hospital (CN)
- Tianjin Medical University (CN)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-10-08
- DOI
- https://doi.org/10.1038/s41598-025-19169-2
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- National Natural Science Foundation of China