Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature.

Abstract

BackgroundGliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to get a mechanistic explanation for this lack of response and to improve the therapy of glial tumors. MethodsWe designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocytrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in mouse glioma models. ResultsWe observed that few immune cells infiltrate mutant IDH1/2 gliomas and we distinguished two different profiles in their IDH1/2 wild-type counterparts. The first one has an important immune component, particularly enriched in myeloid cells with immunosuppressive features. The second group is more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the immune content and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding-protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic mouse glioma models, delaying tumor growth. ConclusionsThere is a correlation between vascular alterations and the immune profile of gliomas, which could be exploited for the design of more successful clinical trials with immunomodulatory molecules. Key pointsO_LIMutant IDH1/2 gliomas harbor few immune cells in the tumor microenviroment. C_LIO_LIWe distinguished two different profiles in the IDH1/2 wild-type gliomas. C_LIO_LIThere is a correlation between Tau expression, vascular alterations and the immune profile. C_LI Importance of the StudyIn the present work we have confirmed that IDHmut gliomas are "cold" tumors and we have identified a subgroup of IDHwt GBMs that also contains a low immune infiltrate. By contrast, a large subgroup of IDHwt GBMs are characterized by an important immune component, particularly enriched in myeloid cells, and an elevated expression of the ligand of PD-L1 in the immune compartment. Notably, we have observed a direct correlation between the immune content and the presence of vascular alterations, as well as with the reduced expression of Tau, a microtubule-binding protein that we described as a negative regulator of angiogenesis. Here, we add that overexpression of Tau reduces the immune content in orthotopic glioma models, delaying tumor growth. This correlation between the vascular phenotype and the entrance and/or the function of the immune cells on gliomas, where Tau could play a central role, opens new venues to find synergistic treatments.