Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment

Jeanmougin, M.; Håvik, Annette Bentsen; Cekaite, Lina; Brandal, Petter; Sveen, Anita; Meling, Torstein R.; Ågesen, Trude H.; Scheie, David; Heim, Sverre; Lind, Guro Elisabeth

doi:10.1002/1878-0261.12668

Cited by 18 publications

(17 citation statements)

References 47 publications

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“…Our detailed characterization of the hematopoietic content of different gliomas suggests that the presence of IDH1/2 mutations, even more than the histological grading, is the best predictor of a reduced immune infiltration in gliomas. This observation is in agreement with the results obtained in mouse models 14 and with the retrospective analysis of human data 7,8,21 . 23 .…”

Section: Discussionsupporting

confidence: 92%

“…our study is conditioned by the limited number of cases included, the results could suggest that the presence of immune cells in the tumor stroma has different consequences in the absence of IDH mutations, as others have proposed21 . Moreover, additional differences, like the ones observed in the vascular compartment, could determine the growth and/or the response to therapy of the two IDHwt subgroups.…”

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confidence: 80%

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

Cejalvo

Gargini

Segura-Collar

et al. 2020

Preprint

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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 hematopoietic 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.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 80%

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

Cejalvo

Gargini

Segura-Collar

et al. 2020

Preprint

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“…Our detailed characterization of the immune content of different gliomas suggests that the presence of IDH1/2 mutations, even more than the histological grading, is the best predictor of a reduced immune in ltration in gliomas. This observation is in agreement with the results obtained in mouse models [14] and with the retrospective analysis of human data [7,8,21]. The paucity of immune cells in IDHmut gliomas could participate in the reduced aggressiveness of IDHmut gliomas, as leukocytes facilitates tumor proliferation [22].…”

Section: Discussionsupporting

confidence: 89%

“…Regarding clinical implications, there are evidences of a possible correlation between the presence of innate immunity cells and the aggressive behavior of gliomas [6]. However, our survival analysis could not detect signi cant differences in the clinical behavior of the two IDHwt GBM subgroups, as other investigators have shown [21]. However, our study is conditioned by the limited number of cases to test survival differences.…”

Section: Discussionmentioning

confidence: 55%

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

Cejalvo

Gargini

Segura-Collar

et al. 2020

Preprint

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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 get a mechanistic explanation for 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 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.Results: We 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. Conclusions: Our results confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. Moreover, we have found that the immunological content distinguishes two groups of IDH1/2 wild-type gliomas, one highly enriched in immunosuppressive cells and one with few lymphocytes and myeloid cells. Our data indicated a direct correlation between the presence of vascular alterations and the entrance of leukocytes in gliomas. 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.

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“…These mutations induce the aberrant phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling ( 2 – 4 ). GB, depending on molecular signatures, is divided into four subtypes, including classical, mesenchymal (MES), neural, and proneural ( 5 ). Among the subtypes, MES shows the most severe drug resistance and frequent mutations of PTEN (37%), accompanied by PI3K/AKT hyperactivation ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

et al. 2020

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Glioblastoma (GB) is the most common and aggressive brain malignancy, characterized by heterogeneity and drug resistance. PTEN, a crucial tumor suppressor, exhibits phosphatase-dependent (PI3K-AKT-mTOR pathway)/independent (nucleus stability) activities to maintain the homeostatic regulation of numerous physiological processes. Premature and absolute loss of PTEN activity usually tends to cellular senescence. However, monoallelic loss of PTEN is frequently observed at tumor inception, and absolute loss of PTEN activity also occurs at the late stage of gliomagenesis. Consequently, aberrant PTEN homeostasis, mainly regulated at the post-translational level, renders cells susceptible to tumorigenesis and drug resistance. Ubiquitination-mediated degradation or deregulated intracellular localization of PTEN hijacks cell growth rheostat control for neoplastic remodeling. Functional inactivation of PTEN mediated by the overexpression of ubiquitin ligases (E3s) renders GB cells adaptive to PTEN loss, which confers resistance to EGFR tyrosine kinase inhibitors and immunotherapies. In this review, we discuss how glioma cells develop oncogenic addiction to the E3s-PTEN axis, promoting their growth and proliferation. Antitumor strategies involving PTEN-targeting E3 ligase inhibitors can restore the tumor-suppressive environment. E3 inhibitors collectively reactivate PTEN and may represent next-generation treatment against deadly malignancies such as GB.

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Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment

Cited by 18 publications

References 47 publications

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

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

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

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

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