Targeting UDP-α-d-glucose 6-dehydrogenase alters the CNS tumor immune microenvironment and inhibits glioblastoma growth

Daqian Zhan; Fatih Yalcin; Ding Ma; Yi Fu; Shuang Wei; Bachchu Lal; Yunqing Li; Omar Dzaye; John Laterra; Mingyao Ying; Hernando Lopez-Bertoni; Shuli Xia

doi:10.1016/j.gendis.2021.08.008

Targeting UDP-α-d-glucose 6-dehydrogenase alters the CNS tumor immune microenvironment and inhibits glioblastoma growth

Genes Dis. 2021 Sep 17;9(3):717-730. doi: 10.1016/j.gendis.2021.08.008. eCollection 2022 May.

Authors

Daqian Zhan^{1

2}, Fatih Yalcin^{3

4}, Ding Ma^{1

5}, Yi Fu¹, Shuang Wei⁶, Bachchu Lal¹, Yunqing Li¹, Omar Dzaye^{3

7}, John Laterra^{1

8}, Mingyao Ying¹, Hernando Lopez-Bertoni¹, Shuli Xia¹

Affiliations

¹ Neurology, Hugo W. Moser Research Institute at Kennedy Krieger, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
³ Department of Radiology and Neuroradiology, Charité, Berlin 10117, Germany.
⁴ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
⁶ University Hospital Center Schleswig Holstein, Department of Neurosurgery, Kiel, Schleswig-Holstein 24105, Germany.
⁷ Departments of Neurology, Oncology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Blood and Cell Therapy Institute, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui 230026, PR China.

Abstract

Glioblastoma (GBM, WHO grade IV glioma) is the most common and lethal malignant brain tumor in adults with a dismal prognosis. The extracellular matrix (ECM) supports GBM progression by promoting tumor cell proliferation, migration, and immune escape. Uridine diphosphate (UDP)-glucose 6-dehydrogenase (UGDH) is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM. We investigated how targeting UGDH in GBM influences the GBM immune microenvironment, including tumor-associated microglia/macrophages (TAMs) and T cells. TAMs are the main immune effector cells in GBM and can directly target tumor cells if properly activated. In co-cultures of GBM cells and human primary macrophages, UGDH knockdown in GBM cells promoted macrophage phagocytosis and M1-like polarization. In orthotropic human GBM xenografts and syngeneic mouse glioma models, targeting UGDH decreased ECM deposition, increased TAM phagocytosis marker expression, reduced M2-like TAMs and inhibited tumor growth. UGDH knockdown in GBM cells also promoted cytotoxic T cell infiltration and activation in orthotopic syngeneic mouse glioma models. The potent and in-human-use small molecule GAG synthesis inhibitor 4-methylumbelliferone (4-MU) was found to inhibit GBM cell proliferation and migration in vitro, mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM. Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvironment.

Keywords: 4-MU; Extracellular matrix (ECM); Glioblastoma (GBM); Hyaluronic acid (HA); Phagocytosis; T cells; Tumor-associated microglia/macrophages (TAMs); UGDH.