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

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Association of IDH mutation and 1p19q co-deletion with tumor immune microenvironment in lower-grade glioma

“…Recently, IDH mutation status has been reported to be associated with PD-L1 expression and tumor-infiltrating lymphocyte (TIL) infiltration in diffuse gliomas. 23 , 24 , 25 , 26 , 27 Our study was largely in agreement with available data but differed in several important aspects. We integrated IDH mutation and 1p/19q codeletion status and conducted a comprehensive and systematic analysis of 28 immune cell types and their infiltration in these subtypes; the expression of the immune checkpoint components in each subtype was assessed and TMB, MSI, and MHC class I gene expression was categorized in these subtypes.…”

Identifies microtubule-binding protein CSPP1 as a novel cancer biomarker associated with ferroptosis and tumor microenvironment

“…High expression of Targeting Protein for Xenopus kinesin-like protein 2 ( TPX2 ) and Tubulin alpha-1C chain ( TUBA1C ) increases immune cell infiltration in LIHC, LUAD, and LGG, respectively, and is associated with poor prognosis [64] , [65] , [66] . A high level of microtubule-associated protein Tau is inversely correlated with the vascular and immune contents, delaying tumor growth in gliomas [67] . Increased expression of microtubule interacting and trafficking domain containing 1 ( MITD1 ) indicates a poor prognosis with decreased NK cell infiltration in LIHC and increased CD8+ T cells infiltration in KIRC [68] , [69] .…”

Integrated analysis of the genomic and transcriptional profile of gliomas with isocitrate dehydrogenase-1 and tumor protein 53 mutations

“…In the LGG cohort, the patients with IDH1 and TP53 mutations seem to have many immunological changes than the patients with wild-type, for example, the anti-viral function (defense response to virus, negative regulation of viral process, and type I interferon signaling pathway), which might indicate that the immune status in the patients with IDH1 and TP53 mutations is different from the patients with wild-type. Previous studies have shown reduced infiltration of immune cells in IDH1 mutant gliomas and suppressed PD-L1 expression, 35 , 36 while TP53 GOF mutation had shown it promotes inflammation and has a profound effect on patient prognosis. 25 In KEGG pathway results, the patients with IDH1 and TP53 mutations suggest more correlation with the other viral infection, such as COVID-19, influenza A, measles, and Epstein-Barr virus, that might be the consequences of the suppression of immune function in these patients.…”