Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors

Kaffes, Ioannis; Szulzewsky, Frank; Chen, Zhihong; Herting, Cameron J.; Gabanic, Ben; Vega, José E. Velázquez; Shelton, J.W.; Switchenko, Jeffrey M.; Ross, James; McSwain, Leon; Huse, Jason T.; Westermark, Bengt; Nelander, Sven; Forsberg-Nilsson, Karin; Uhrbom, Lene; Maturi, Naga Prathyusha; Cimino, Patrick J.; Holland, Eric C.; Kettenmann, Helmut; Brennan, Cameron; Brat, Daniel J.; Hambardzumyan, Dolores

doi:10.1080/2162402x.2019.1655360

Cited by 92 publications

(107 citation statements)

References 73 publications

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“…Notably, the expression of PN or MES markers did not allow us to distinguish between these two immune subtypes of GBMs. These results differ from some computational [7] and IHC [9,10] studies, showing the enrichment of myeloid and lymphoid cells in the MES subtype. Another study, however, observed an accumulation of CL tumors among GBMs with a high immune in ltrate [8].…”

Section: Discussioncontrasting

confidence: 99%

“…Nonetheless, gliomas are far from being a homogenous entity and disparities in their immune content might also condition their response to different therapeutic strategies. In order to classify the immunological pro le of glial tumors, several groups have used computational and immunohistochemical (IHC) analysis approaches [7][8][9][10]. Here, we have performed a comprehensive characterization of the tumors by ow cytometry.…”

Section: Introductionmentioning

confidence: 99%

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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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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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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…They also displayed significantly higher expression of immune checkpoints such as PDL1 , in line with Liu et al (2017), and CTLA4, indicating they could be good candidates for immune checkpoint inhibitors therapies. Although others have previously reported similar finding in mesenchymal tumors (Chen and Hambardzumyan, 2018; Doucette et al , 2013; Kaffes et al , 2019), we provide here an alternative strategy based on unsupervised learning, without making any prior assumption on the tumor molecular subtypes. Our approach enables to identify tumors from other molecular subtypes presenting a similar immune and stromal phenotype, which could also benefit from treatments targeting the microenvironment.…”

Section: Discussionmentioning

confidence: 87%

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

et al. 2020

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Glioblastoma (GBM), the most aggressive form of brain cancer, is characterized by a high level of molecular heterogeneity, and infiltration by various immune and stromal cell populations. Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. We have investigated the abundance of infiltrating immune and stromal cells in silico, from gene expression profiles. Two cohorts, including in-house normal brain and glioma samples (n = 70) and a large sample set from TCGA (n = 393), were combined into a single exploratory dataset. A third independent cohort (n = 124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. We identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes with improving prognostic models in GBM.

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“…Similar expression patterns were also reported for other immune checkpoints such as PD-L1 [29], B7-H3 [26], TIM-3 [27], CD155 [30], and PTPN2 [28] in glioma. Besides, Kaffes et al found highest immune cells presence in mesenchymal GBM compared with other subtypes [31]. These results suggested mesenchymalsubtype gliomas may be more amenable to immunotherapy.…”

Section: Discussionmentioning

confidence: 95%

CTLA-4 correlates with immune and clinical characteristics of glioma

Liu

Huang

Liu³

et al. 2020

Cancer Cell Int

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Background: CTLA-4 is a well-studied immune checkpoint protein that negatively regulates T cell-mediated immune responses. However, the expression of CTLA-4 in glioma and the effects of CTLA-4 on prognosis in patients with glioma have not yet been examined. Methods: We investigated the protein level of CTLA-4 in human glioma samples, extracted genetic and clinical data from 1024 glioma patients to characterize CTLA-4 expression and its relationship with immune functions in gliomas. R language was used for statistical analysis. Results: Higher CTLA-4 expression was found in patients with higher grade, isocitrate dehydrogenase (IDH)-wildtype, and mesenchymal-molecular subtype gliomas than in patients with lower grade, IDH-mutant, and other molecular subtype gliomas. Further analysis showed that there was a strong positive correlation between CTLA-4 and the specific marker gene expression of immune cells, including CD8 + T cells, regulatory T cells, and macrophages in both databases, suggesting that higher CTLA-4 expression in the glioma microenvironment induced greater immune cell infiltration compared with that in gliomas with lower CTLA-4 expression. We further explored the associations between CTLA-4 and other immune-related molecules. Pearson correlation analysis showed that CTLA-4 was associated with PD-1, CD40, ICOS, CXCR3, CXCR6, CXCL12 and TIGIT. Patients with glioma with lower CTLA-4 expression exhibited significantly longer overall survival. Thus, these findings suggested that increased CTLA-4 expression conferred a worse outcome in glioma. Conclusions: In summary, our findings revealed the expression patterns and clinical characteristics of CTLA-4 in glioma and may be helpful for expanding our understanding of antitumor immunotherapy in gliomas.

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Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors

Cited by 92 publications

References 73 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.

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

CTLA-4 correlates with immune and clinical characteristics of glioma

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