ASGR2 AND CLEC12A C TYPE LECTINS: NEW PLAYERS IN GLIOBLASTOMA IMMUNOSUPPRESSIVE NETWORKS

BACKGROUND-AIM Glioblastoma (GBM) is the most fathal brain tumor in adults with poor survival and no effective treatment. Dissecting immunosuppressive mechanisms in GBM is crucial to identify novel therapeutic targets. Lectins are glycan-binding immune receptors, that promote immunosuppression in cancer. Little is known about lectin immune receptors (C-type lectins, Siglecs, galectins) and their role in GBM. Here, we aim to identify novel lectins that could be relevant in GBM immunosuppression. METHODS Differential network analysis was performed using publicly available databases (TCGA and CGGA for IDH-WT GBM; GTEx for normal brain)to identify lectins positively coordinated in GBM. Based on the lectins’ expression, patients’ subgroups were identified using Fuzzy C-means algorithm and survival analysis was performed. To validate the identified lectin expression profile on immune cell subsets, patients-derived tumor samples (10) were freshly processed to obtain a single cell suspension and analyzed by flow cytometry. RESULTS Differential co-expression network between TCGA and GTEx identified a community of lectins, whose coordination was increased in GBM. ASGR2 and CLEC12A emerged as the strongest hubs in the network. To validate our finding, we performed the differential network analysis on CGGA, that confirmed ASGR2 and CLEC12A as the strongest hubs. Up today, no evidences are available on ASGR2 and CLEC12A role in GBM, so we characterized for the first time their expression on immune cells in patients-derived GBM tumors. We found that intratumoral CD45+ cells express both ASGR2 and CLEC12A, while CD45- cells are negative. ASGR2 is predominantly expressed by infiltrating macrophages than resident microglia (p<0.05). CLEC12A is associated to both infiltrating and resident immune cells. Stratifying patients based on ASGR2 and CLEC12A expression, we found that high levels of ASGR2-CLEC12A correlated with the worst prognosis (p<0.05). CONCLUSIONS Ourresults show forthe firsttime the expression of ASGR2 and CLEC12A exclusively on immune infiltrate in GBM. These lectins belong to C-type lectin family, that has been poorly investigated in GBM. Given their association with immune infiltrating cells, ASGR2 and CLEC12A could be relevant and contribute to GBM immunosuppression.