Glioblastomas exploit truncated O-linked glycans for local and distant immune modulation via the macrophage galactose-type lectin

Sophie A. Dusoswa, Jan Verhoeff, Erik Abels, Santiago P. Méndez-Huergo, Diego O. Croci, Lisan H. Kuijper, Elena de Miguel, Valerie M.C.J. Wouters, Myron G. Best, Ernesto Rodriguez, Lenneke A.M. Cornelissen, Sandra J. van Vliet, Pieter Wesseling, Xandra O. Breakefield, David P. Noske, Thomas Würdinger, Marike L.D. Broekman, Gabriel A. Rabinovich*, Yvette van Kooyk, Juan J. Garcia-Vallejo

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Glioblastoma is the most aggressive brain malignancy, for which immunotherapy has failed to prolong survival. Glioblastoma-associated immune infiltrates are dominated by tumor-associated macrophages and microglia (TAMs), which are key mediators of immune suppression and resistance to immunotherapy. We and others demonstrated aberrant expression of glycans in different cancer types. These tumor-associated glycans trigger inhibitory signaling in TAMs through glycan-binding receptors. We investigated the glioblastoma glycocalyx as a tumor-intrinsic immune suppressor. We detected increased expression of both tumor-associated truncated O-linked glycans and their receptor, macrophage galactose-type lectin (MGL), on CD163+ TAMs in glioblastoma patient-derived tumor tissues. In an immunocompetent orthotopic glioma mouse model overexpressing truncated O-linked glycans (MGL ligands), high-dimensional mass cytometry revealed a wide heterogeneity of infiltrating myeloid cells with increased infiltration of PD-L1+ TAMs as well as distant alterations in the bone marrow (BM). Our results demonstrate that glioblastomas exploit cell surface O-linked glycans for local and distant immune modulation.

Original languageEnglish
Pages (from-to)3693-3703
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number7
DOIs
Publication statusPublished - 18 Feb 2020

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