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

Raimond Heukers, Tian Shu Fan, Raymond H. de Wit, Jeffrey R. van Senten, Timo W. M. de Groof, Maarten P. Bebelman, Tonny Lagerweij, Joao Vieira, Sabrina M. de Munnik, Laura Smits-de Vries, Jody van Offenbeek, Afsar Rahbar, Diane van Hoorick, Cecilia Söderberg-Naucler, Thomas Würdinger, Rob Leurs, Marco Siderius, Henry F. Vischer, Martine J. Smit

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)4110-4121
JournalOncogene
Volume37
Issue number30
DOIs
Publication statusPublished - 2018

Cite this

Heukers, R., Fan, T. S., de Wit, R. H., van Senten, J. R., de Groof, T. W. M., Bebelman, M. P., ... Smit, M. J. (2018). The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth. Oncogene, 37(30), 4110-4121. https://doi.org/10.1038/s41388-018-0255-7