Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype.

Gliomas 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 explain this lack of response and to improve the therapy of glial tumors. We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate 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 syngeneic mouse models. We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes 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 allografts of GL261 cells, delaying tumor growth. We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.Work was supported by Ministerio de Economía y Competitividad: (Acción Estratégica en Salud) and FEDER (fondo europeo de desarrollo regional) funds: PI13/01258 to AHL and PI17/01621 to J.M.S.-S.; by AECC (Asociación Española contra el Cancer) grants: Investigador Junior to R.G. and GCTRA16015SEDA to J.M.S.-S.; by Ministerio de Ciencia, Innovación y Universidades and FEDER funds: RTI2018-093596 to P.S.-G.; by FSEOM (Fundación Sociedad Española de Oncología Médica) grant to J.M.S.-S.S