2. Academic Validation
  3. Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma

Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma

  • Cell Death Discov. 2022 Apr 11;8(1):193. doi: 10.1038/s41420-022-00973-y.
Tao Yan  # 1 2 3,  Kaikai Wang  # 4,  Jiafeng Li  # 1 2 3,  Hong Hu  # 1 2 3,  He Yang 1 2 3,  Meng Cai 1 2 3,  Ruijie Liu 1 2 3,  Honglei Li 1 2 3,  Ning Wang 5,  Ying Shi 6,  Wei Hua 7,  Huailei Liu 8 9 10
Affiliations

Affiliations

  • 1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, China.
  • 3 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, China.
  • 4 Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 5 Department of Critical Care Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 6 Department of Radiology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 7 Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 8 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China. liuhuaileinsdm@hrbmu.edu.cn.
  • 9 Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin, China. liuhuaileinsdm@hrbmu.edu.cn.
  • 10 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, China. liuhuaileinsdm@hrbmu.edu.cn.
  • # Contributed equally.
PMID: 35410993 DOI: 10.1038/s41420-022-00973-y
Abstract

Immunosuppressive tumor microenvironment is a crucial factor that impedes the success of tumor immunotherapy, and tumor-associated macrophages (TAMs) are essential for the formation of tumor immunosuppressive microenvironment. Hyaluronic acid (HA) is highly important brick for glioblastoma microenvironment, but whether it contributes to TAM polarization and glioblastoma immunosuppressive microenvironment is less well known. In our study, we observed that disrupting glioblastoma HA synthesis or blocking HA binding to its receptor CD44 on macrophages increased the proportion of M1 macrophages by upregulating SIRPα in macrophages, the underlying mechanism was elevated SIRPα enhanced STAT1 phosphorylation and suppressed STAT3 phosphorylation in macrophages. Subsequently, the induced macrophages could inhibit glioblastoma growth via a feedback effect. In addition, 4-methylumbelliferone (4MU), a cholecystitis drug, can disrupt the CD47/SIRPα axis by disturbing glioblastoma HA synthesis. Collectively, these findings indicated that HA plays a crucial role in macrophages polarization and CD47/SIRPα signaling between glioblastoma cells and macrophages, and suppressing the HA pathway may be a new immunotherapeutic approach for glioblastoma.

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