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Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas

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Abstract

In order to clarify the role of endothelin B receptors (ETBRs) in gliomas, we analyzed cell cultures and surgical specimens of gliomas using RT-PCR and immunohistochemistry. RT-PCR measured the absolute expression of ETBR mRNA in twelve samples, which included gliomas that were classified using the World Health Organization (WHO) classification system Grade I–IV, as well as two glioblastoma cell lines (CCF-STTG1 and U87-MG). Using immunohistochemistry, 77 glioma specimens were evaluated for their expression of ETBR and infiltrating T lymphocytes, including an analysis of cytotoxic T cells (CTLs) and regulatory T lymphocytes (Tregs). The number of ETBR-positive vessels in the glioblastomas (Grade IV) was significantly higher than in other grades of gliomas (comparisons to Grade IV, Grade I: p = 0.0323, Grade II: p = 0.0009, Grade III: p = 0.0273). The ETBR expression rate (defined as the number of ETBR-positive blood vessels divided by the total number of blood vessels) in the glioblastomas was higher than the ETBR expression rate in the low-grade gliomas (compared to Grade IV, Grade I: p = 0.0132, Grade II: p = 0.0018, Grade III: p = 0.0745). In addition, the cases which had an ETBR expression rate of 50 % or higher exhibited fewer infiltrating CTLs and more infiltrating Tregs compared to the cases with an ETBR expression rate <50 % (CTLs: p = 0.0342; Tregs: p = 0.0175). Isocitrate dehydrogenase 1 (IDH-1) mutations were identified in 21 cases, but there was no correlation between ETBR expression and IDH-1 mutations for any WHO grade. These results suggest that ETBR expression during neo-angiogenesis may interfere with the homing of CTLs around the tumor and be involved in the immune escape mechanism of gliomas.

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Acknowledgement

We thank Professor Elias Campo and his department members for providing antibodies. This work was supported by JSPS KAKENHI Grant Number 24500427.

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Authors and Affiliations

  1. Department of Pathology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan

    Shinji Nakashima, Yasuo Sugita, Hiroaki Miyoshi, Fumiko Arakawa, Hiroko Muta, Yukinao Ishibashi, Daisuke Niino & Koichi Ohshima

  2. Department of Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan

    Shinji Nakashima, Mizuhiko Terasaki, Yukihiko Nakamura & Motohiro Morioka

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  1. Shinji Nakashima
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  2. Yasuo Sugita
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Correspondence to Shinji Nakashima.

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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. For this type of study, formal consent was not required.

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Nakashima, S., Sugita, Y., Miyoshi, H. et al. Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas. J Neurooncol 127, 23–32 (2016). https://doi.org/10.1007/s11060-015-2017-5

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  • DOI: https://doi.org/10.1007/s11060-015-2017-5

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