Journal of Neuro-Oncology

, Volume 146, Issue 2, pp 265–273 | Cite as

Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas

  • Ryota Tamura
  • Yukina Morimoto
  • Mizuto Sato
  • Yuki Kuranari
  • Yumiko Oishi
  • Kenzo Kosugi
  • Kazunari Yoshida
  • Masahiro TodaEmail author
Laboratory Investigation



Neurofibromatosis type 2 (NF2) patients uniformly develop multiple schwannomas. The tumor-microenvironment (TME) is associated with hypoxia and consists of immunosuppressive cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). The hypoxic TME of NF2 schwannomas remains unclear. In addition, no comparative study has investigated immunosuppressive cells in NF2 and sporadic schwannomas.


In 22 NF2 and 21 sporadic schwannomas, we analyzed the immunohistochemistry for Ki-67, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, platelet derived growth factor receptor-beta (PDGFR-β), programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1), Foxp3, CD163, CD3, and CD8 to assess the immunosuppressive TME.


Most vessels in sporadic schwannomas exhibited slight or negative VEGFR1 and 2 expressions with pericytes coverage. In contrast, large vessels in NF2 schwannomas exhibited strong VEGFR1 and 2 expressions without pericytes. The number of CD3+, CD8+, and CD163+ cells was significantly higher in NF2 schwannomas than in sporadic ones. The expression of PD-L1 and nestin positive cell ratio was higher in NF2 schwannomas than that in sporadic ones. The number of CD163+ cells, nestin positive cell ratio, and HIF-1α expression were significantly associated with shorter progression-free survival in NF2 schwannomas.


This study presents the clinicopathological features of the differences in immunosuppressive cells and the expression of immune checkpoint molecules between NF2 and sporadic schwannomas. Hypoxic TME was first detected in NF2-schwannomas, which was associated with the tumor progression.


NF2 Schwannoma Hypoxia PD-1 PD-L1 Treg: TAM 



The authors greatly thank Ms. Naoko Tsuzaki at Department of Neurosurgery, Keio University School of Medicine, for technical assistance of laboratory works.


This work was supported in part by grants from the Japan Society for the Promotion of Science (JSPS) (17H04306 to M.T.), and by the Japan Agency for Medical Research and Development (19lm0203088h0001 to M.T.).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of NeurosurgeryKeio University School of MedicineTokyoJapan

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