Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction

  • Cell Death Dis. 2021 Apr 7;12(4):373. doi: 10.1038/s41419-021-03664-1.
Jianye Xu   #  1  2 ,  Jian Zhang   #  1  2  3 ,  Zongpu Zhang  1  2 ,  Zijie Gao  1  2 ,  Yanhua Qi  1  2 ,  Wei Qiu  1  2 ,  Ziwen Pan  1  2 ,  Qindong Guo  1  2 ,  Boyan Li  1  2 ,  Shulin Zhao  1  2 ,  Xiaofan Guo  1  2 ,  Mingyu Qian  1  2 ,  Zihang Chen  1  2 ,  Shaobo Wang  1  2 ,  Xiao Gao  1  2 ,  Shouji Zhang  1  2 ,  Huizhi Wang  1  2 ,  Xing Guo  1  2 ,  Ping Zhang  1  2 ,  Rongrong Zhao  1  2 ,  Hao Xue  4  5 ,  Gang Li  6  7
Affiliations
  • 1. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China.
  • 2. Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012, Shandong, China.
  • 3. Department of Neurosurgery, Dezhou People's Hospital, Dezhou, 253000, Shandong, China.
  • 4. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China. [email protected].
  • 5. Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012, Shandong, China. [email protected].
  • 6. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China. [email protected].
  • 7. Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012, Shandong, China. [email protected].
  • # Contributed equally.
PMID: 33828078 DOI: 10.1038/s41419-021-03664-1
Abstract

Exosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on Autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated Autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence Autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting Autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

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