Introduction Aberrant glycosylation sustains tumor progression and immunogenicity1. Alterations in the mucin O-glycosylation pathway generate truncated Tn and its sialylated form STn antigens. Tn is recognized by the C-type Macrophage Galactose-Type Lectin (MGL) expressed on dendritic cells and macrophages (MDM). MGL-Tn interactions negatively modulate the antitumor immune response and promote tumor evasion, thus their targeting has been proposed as immunotherapeutic approach in cancer1. Glioblastoma (GB) is the most aggressive and still untreatable brain tumor. Hypoxia, impaired angiogenesis and immunosuppressive cells (myeloid-derived suppressor cells (MDSC), microglia (MG), MDM) contribute to mediate the immunotherapy resistance1. In an engineered Tn-expressing GB mouse model, the ortholog mgl1 has been detected on CD163+ PD-L1+ MDM2, while no evidence is available in human GB2. Dissecting the immunosuppressive mechanisms in GB is crucial to identify novel therapeutic targets. Methods Patient derived tumor samples (15 GB;3 low-grade glioma (LGG)) were collected at the Neurosurgery Dpt, Umberto I Hospital in Rome, and freshly processed as single cell suspension to characterize MGL expression on the different immune cell subsets (MDSC, MDM, MG) by flow-cytometry. Tn, STn and CD163 expression was analyzed on formalin-fixed paraffin embedded (FFPE) tissue sections (26 GB, 8 LGG) by IHC. Results Our preliminary results show that MGL is heterogeneously expressed on myeloid immune cells and its overall expression is higher in GB vs LGG. Interestingly, MGL is expressed not only by MDM, but also by MDSCs and MG. In accordance, Tn antigen displayed a similar expression profile by being only captured in GB and in association to neoplastic cells, while it was completely absent in LGG. Tn expression positively correlates to CD163 expression in GB. STn was expressed in both GB and LGG microenvironment in correspondence of vasculature compartment. Conclusions Our results suggest that, depending on the spatial and cellular distribution, MGL-Tn axis may be relevant in immunosuppression in GB. Further studies are required to evaluate the impact of MGL engagement by the two ligands on the immunosuppressive cells. The MGL-Tn axis may represent a novel therapeutic strategy for GB.
MGL lectin receptor and immunosuppression networks in glioblastoma / Pace, Angelica; Scirocchi, Fabio; Rahimi, Hassan; Minasi, Simone; Napoletano, Chiara; Asquino, Angela; Zizzari, ILARIA GRAZIA; D’Angelo, Luca; Santoro, Antonio; Buttarelli, Francesca; Nuti, Marianna; Rughetti, Aurelia. - (2023). (Intervento presentato al convegno Young Scientists Meeting 2023 GENERAL PATHOLOGY:THE TRUNK OF THE TREE OF MEDICINE tenutosi a Parma).
MGL lectin receptor and immunosuppression networks in glioblastoma
Angelica Pace;Fabio Scirocchi;Hassan Rahimi;Simone Minasi;Chiara Napoletano;Angela Asquino;Ilaria Grazia Zizzari;Francesca Buttarelli;Marianna Nuti;Aurelia Rughetti
2023
Abstract
Introduction Aberrant glycosylation sustains tumor progression and immunogenicity1. Alterations in the mucin O-glycosylation pathway generate truncated Tn and its sialylated form STn antigens. Tn is recognized by the C-type Macrophage Galactose-Type Lectin (MGL) expressed on dendritic cells and macrophages (MDM). MGL-Tn interactions negatively modulate the antitumor immune response and promote tumor evasion, thus their targeting has been proposed as immunotherapeutic approach in cancer1. Glioblastoma (GB) is the most aggressive and still untreatable brain tumor. Hypoxia, impaired angiogenesis and immunosuppressive cells (myeloid-derived suppressor cells (MDSC), microglia (MG), MDM) contribute to mediate the immunotherapy resistance1. In an engineered Tn-expressing GB mouse model, the ortholog mgl1 has been detected on CD163+ PD-L1+ MDM2, while no evidence is available in human GB2. Dissecting the immunosuppressive mechanisms in GB is crucial to identify novel therapeutic targets. Methods Patient derived tumor samples (15 GB;3 low-grade glioma (LGG)) were collected at the Neurosurgery Dpt, Umberto I Hospital in Rome, and freshly processed as single cell suspension to characterize MGL expression on the different immune cell subsets (MDSC, MDM, MG) by flow-cytometry. Tn, STn and CD163 expression was analyzed on formalin-fixed paraffin embedded (FFPE) tissue sections (26 GB, 8 LGG) by IHC. Results Our preliminary results show that MGL is heterogeneously expressed on myeloid immune cells and its overall expression is higher in GB vs LGG. Interestingly, MGL is expressed not only by MDM, but also by MDSCs and MG. In accordance, Tn antigen displayed a similar expression profile by being only captured in GB and in association to neoplastic cells, while it was completely absent in LGG. Tn expression positively correlates to CD163 expression in GB. STn was expressed in both GB and LGG microenvironment in correspondence of vasculature compartment. Conclusions Our results suggest that, depending on the spatial and cellular distribution, MGL-Tn axis may be relevant in immunosuppression in GB. Further studies are required to evaluate the impact of MGL engagement by the two ligands on the immunosuppressive cells. The MGL-Tn axis may represent a novel therapeutic strategy for GB.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
