Glioblastomas exploit truncated O-linked glycans for local and distant immune modulation via the macrophage galactose-type lectin
Menée in vitro et à l'aide d'un modèle murin de gliome, cette étude démontre que les glioblastomes exploitent les O-glycanes tronqués de leurs cellules pour réguler la réponse immunitaire locale ou distante via les lectines MGL (macrophage galactose-type lectin) des cellules microgliales et des macrophages associés à la tumeur
Immunotherapy clinical trials have shown promising results only in some glioblastoma patients, warranting further research on glioblastoma-induced immune suppression. Cancer-driven changes in glycosylation are beginning to be appreciated as key modulators of cancer immune evasion, since antigen-presenting cells express glycan-recognizing receptors that trigger immune-suppressive signaling upon interaction with their ligands. Here we identify an O-linked glycan signature, characterized as a ligand of the tolerogenic C-type lectin receptor MGL, as modulator of immune suppression in glioblastoma. An in vivo model showed that overexpression of the MGL ligand in glioblastoma led to increased infiltration of PD-L1+ macrophages, which could also be found in patient-derived glioblastoma tissues. An improved understanding of the glioblastoma glyco-code could lead to new prognostic and therapeutic clinical applications.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.