Glioblastoma may evade immune surveillance through primary cilia-dependent signaling in an IL-6 dependent manner

Maxwell T Laws; Erin N Walker; Francesca M Cozzi; Leonel Ampie; Mi-Yeon Jung; Eric C Burton; Desmond A Brown

doi:10.3389/fonc.2023.1279923

Glioblastoma may evade immune surveillance through primary cilia-dependent signaling in an IL-6 dependent manner

Front Oncol. 2023 Dec 18:13:1279923. doi: 10.3389/fonc.2023.1279923. eCollection 2023.

Authors

Maxwell T Laws^#¹, Erin N Walker^#^{1

2}, Francesca M Cozzi³, Leonel Ampie¹, Mi-Yeon Jung¹, Eric C Burton^{1

4}, Desmond A Brown¹

Affiliations

¹ Neurosurgical Oncology Unit, Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
² University of South Carolina School of Medicine Greenville, Greenville, SC, United States.
³ Cambridge Brain Tumour Imaging Lab, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbroke's Hospital, Cambridge, United Kingdom.
⁴ Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

^# Contributed equally.

Abstract

Glioblastoma is the most common, malignant primary brain tumor in adults and remains universally fatal. While immunotherapy has vastly improved the treatment of several solid cancers, efficacy in glioblastoma is limited. These challenges are due in part to the propensity of glioblastoma to recruit tumor-suppressive immune cells, which act in conjunction with tumor cells to create a pro-tumor immune microenvironment through secretion of several soluble factors. Glioblastoma-derived EVs induce myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs) from myeloid precursors leading to systemic and local immunosuppression. This process is mediated by IL-6 which contributes to the recruitment of tumor-associated macrophages of the M2 immunosuppressive subtype, which in turn, upregulates anti-inflammatory cytokines including IL-10 and TGF-β. Primary cilia are highly conserved organelles involved in signal transduction and play critical roles in glioblastoma proliferation, invasion, angiogenesis, and chemoradiation resistance. In this perspectives article, we provide preliminary evidence that primary cilia regulate intracellular release of IL-6. This ties primary cilia mechanistically to tumor-mediated immunosuppression in glioblastomas and potentially, in additional neoplasms which have a shared mechanism for cancer-mediated immunosuppression. We propose potentially testable hypotheses of the cellular mechanisms behind this finding.

Keywords: CCRK; IL-6; extracellular vesicles; glioblastoma; glioblastoma-mediated immunosuppression; primary cilia.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported financially by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke and the National Cancer Institute in Bethesda, Maryland.