Network analysis to unveil lectins-mediated immunosuppression in glioblastoma

Glioblastoma is the most aggressive brain tumor in adults with devastating outcomes and no effective treatment1. Glycans-lectin interactions modulate immune responses, promoting immunosuppression2-5. Little is known about lectin immune receptors (C-type lectins, Siglecs, galectins) and their role in glioblastoma6. Here, we aim to investigate lectins in glioblastoma immunosuppressive network and identify novel therapeutic targets. Gene co-expression networks and differential network analysis were performed using publicly available databases (TCGA for IDH-WT-glioblastoma data; GTex for healthy subjects data) to identify lectins relevant in glioblastoma. Based on the lectins’ expression level, patients’ subgroups were identified using Fuzzy C-means algorithm and survival analysis was performed. Differential co-expression network analysis between glioblastoma and healthy brain tissue, identified a community of positively correlated lectins (ASGR2, LGALS8, CLEC4A, SIGLEC7, CLEC7A, SIGLEC10, SIGLEC11, CLEC12A) whose coordination was increased in glioblastoma. High levels of ASGR2-LGALS8-SIGLEC7 correlated with the worst prognosis(p=0,034). A trend of negative correlation with survival was also observed for ASGR2-CLEC4A(p=0.053) and ASGR2-SIGLEC7(p=0.063). Our results show that ASGR2, LGALS8, SIGLEC7, CLEC4A could be relevant in glioblastoma, correlating to worst outcome. Interestingly, these lectins belong to three different families and are selectively expressed by myeloid, lymphoid and tumor cells, thus suggesting their possible role as interplayers among the distinct GBM cell components promoting and enhancing immunosuppression. Indeed, in glioblastoma SIGLEC7 has been associated to suppressive cells and LGALS8 has shown to promote resistance of glioblastoma cell lines. Understanding how lectins interplay could promote immunosuppression within GBM microenvironment might strongly contribute to identify novel targets and therapeutic interventions for glioblastoma.