Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells

Klemm, Florian; Maas, Roeltje R.; Bowman, Robert L.; Kornete, Mara; Soukup, Klara; Nassiri, Sina; Brouland, Jean‐Philippe; Iacobuzio‐Donahue, Christine A.; Brennan, Cameron; Tabar, Viviane; Gutin, Philip H.; Daniel, Roy Thomas; Hegi, Monika E.; Joyce, Johanna A.

doi:10.1016/j.cell.2020.05.007

Cited by 713 publications

(817 citation statements)

References 93 publications

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“…Notably, no clear differences were found in the amount of microglia amid the different subgroups. Our results are in agreement with recently published data showing that the main immune signature in IDHmut gliomas correspond to microglia, whereas in the wild-type tumors there is an accumulation of in ltrating myeloid and T cells [25]. Notably, we have found a high level of expression of CD206, a marker of pro-tumoral M2 macrophages, in myeloid cells in the GBMwt_high tumors, and a strong increase in PD-L1 expression between this subgroup and the rest of gliomas.…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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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“…Finally, indication for a tumor-suppressive activity of the NOTCH pathway in glioma predominantly comes from an in vivo immunocompetent setting, and a recent CRISPR screen identified frequent co-mutation of the NOTCH1 receptor and B2m, an essential component of the MHC-I antigen presentation complex [ 150 ]. Interestingly, findings indicate that the immune response to cancer in the brain is shaped by the cancer type [ 165 , 166 ]. Whether NOTCH activity in tumor cells can regulate interactions with the glioma microenvironment and immune evasion remains unexplored.…”

Section: Open Questions and Perspectivesmentioning

confidence: 99%

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Parmigiani

Taylor

Giachino

2020

Cells

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Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we illustrate the context-dependent role of NOTCH signaling during tumorigenesis with a particular focus on gliomas, the most frequent and aggressive brain tumors in adults. For a long time, NOTCH has been considered an oncogene in glioma mainly by virtue of its neural stem cell-promoting activity. However, the recent identification of NOTCH-inactivating mutations in some glioma patients has challenged this notion, prompting a re-examination of the function of NOTCH in brain tumor subtypes. We discuss recent findings that might help to reconcile the controversial role of NOTCH signaling in this disease, and pose outstanding questions that still remain to be addressed.

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“…During neurological disease, the breakdown of the BBB allows T-cells, among others, to enter the brain [ 123 , 138 ]. Compared to GBM, metastatic brain tumors have a substantially higher number of infiltrating lymphocytes [ 139 ]. While this process could lead to the elimination of a tumor, it often allows tumor-promoting populations to enter the brain such as regulatory T-cells (Tregs).…”

Section: Immune Traffickingmentioning

confidence: 99%

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

et al. 2020

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Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood–brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P.

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Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells

Cited by 713 publications

References 93 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.

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

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