The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth

• Published in: Oncogene Vol. 37; no. 30; pp. 4110 - 4121
• Main Authors: Heukers, Raimond, Fan, Tian Shu, de Wit, Raymond H., van Senten, Jeffrey R., De Groof, Timo W. M., Bebelman, Maarten P., Lagerweij, Tonny, Vieira, Joao, de Munnik, Sabrina M., Smits-de Vries, Laura, van Offenbeek, Jody, Rahbar, Afsar, van Hoorick, Diane, Söderberg-Naucler, Cecilia, Würdinger, Thomas, Leurs, Rob, Siderius, Marco, Vischer, Henry F., Smit, Martine J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2018; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/21; 13/31; 13/51; 14/63; 38/109; 59/5; 59/57; 631/154/555; 631/67/1059/602; 631/67/1858; 631/67/1922; 64/60; 82/1; 82/80; 82/83; 96/106; 96/109; 96/21; 96/44; Apoptosis; Brain cancer; Brain tumors; Cancer; Care and treatment; Cell Biology; Cell receptors; Chemokines; Deoxyribonucleic acid; Development and progression; Displays (Marketing); DNA; Gene expression; Genetic aspects; Glioblastoma; Glioblastoma cells; Glioblastomas; Gliomas; Health aspects; Human Genetics; Inflammation; Innovations; Internal Medicine; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Molecular targeted therapy; Nanobodies; Neurospheres; Oncology; Proteins; Spheroids; Tumors
• DOI: 10.1038/s41388-018-0255-7
• ISSN: 0950-9232; 1476-5594

Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251− and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.