GLIOBLASTOMAS EXPLOIT TRUNCATED O-LINKED GLYCANS FOR LOCAL AND DISTANT IMMUNE MODULATION VIA THE MACROPHAGE GALACTOSE-TYPE LECTIN

SOPHIE A. DUSOSWA; SANTIAGO P. MENDEZ HUERGO; ELENA DE MIGUEL; ERNESTO RODRIDUEZ; PIETER WESSELING; THOMAS WÜRDINGER; YVETTE VAN KOOYK; JAN VERHOEFF; DIEGO O. CROCI; VALERIE M.C.J. WOUTERS; LENNEKE A.M. CORNELISSEN; XANDRA O. BREAKEFIELD; MARIKE L.D. BROEKMAN; JUAN J. GARCÍA-VALLEJO; ERIK ABELS; LISAN H. KUIJPER; MYRON G. BEST; SANDRA VAN VLIET; DAVID P. NOSKE; GABRIEL RABINOVICH (*}

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2020

0027-8424

Glioblastoma is the most aggressive brain malignancy, for which immunotherapy has failed to prolong survival. Glioblastoma-associated immune infiltrates are dominated by tumour-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 tumour-associated glycans trigger inhibitory signalling in TAMs through glycan-binding receptors. We investigated the glioblastoma glycocalyx as a tumour-intrinsic immune suppressor. We detected increased expression of both tumour-associated truncated O-linked glycans and their receptor, macrophage galactose-type lectin (MGL), on CD163+ TAMs in glioblastoma patient-derived tumour tissues. In an immunocompetent orthotopic glioma mouse model over-expressing 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. Key words: Glioblastoma, glioma, MGL, O-linked glycosylation, Tn antigen, Cosmc, C1galt1c1, immune regulation, macrophages.* Corresponding authors: GAR and JJGV