Immune classifications with cytotoxic CD8<sup>+</sup> and Th17 infiltrates are predictors of clinical prognosis in glioblastoma

Madkouri, Rachid; Kaderbhai, C.; Bertaut, Aurélie; Truntzer, Caroline; Vincent, Julie; Aubriot-Lorton, M.-H.; Farah, Walid; Limagne, Emeric; Ladoire, Sylvain; Boidot, Romain; Dérangère, Valentin; Ghiringhelli, François

doi:10.1080/2162402x.2017.1321186

Cited by 27 publications

(27 citation statements)

References 31 publications

(36 reference statements)

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“…The gene signatures proposed by Becht et al have been carefully selected to be specific for the described immune cell populations and validated in several thousand tumors including a small dataset of medulloblastoma. 26 A study of CD8 and Th17 infiltrates in GBM 30 showed comparable associations with prognosis of immunohistological data and data based on gene expression signatures in a similar approach to those proposed by Becht et al Further, intratumoral heterogeneity of gene expression in medulloblastoma is very low, 31 which also supports our assumption that transcriptome based analysis is suitable for a global description of the tumor microenvironment. However, it cannot be excluded that tumor cells contribute to the expression score, which might significantly confound the analysis.…”

Section: Discussionsupporting

confidence: 84%

Subgroup-specific immune and stromal microenvironment in medulloblastoma

et al. 2018

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Knowledge on immune and stromal cells in medulloblastoma microenvironment is still limited as previous work was frequently restricted by low sample size and the lack of molecular subgroup information. We characterized 10 microenvironment cell populations as well as from gene expression in 1422 brain tumors and 763 medulloblastomas. All in all, medulloblastomas showed low expression of immune markers. Still, there were substantial differences with a clustering of medulloblastoma subgroups according to their microenvironment profile. Specifically, SHH medulloblastomas displayed strong signatures of fibroblasts, T cells and macrophages, while markers of cytotoxic lymphocytes were enriched in Group 4 tumors. gene expression appeared to be relatively high in single SHH and WNT cases but was undetectable by immunohistochemistry. In addition, two diverse immuno-stromal patterns were identified, indicating distinct types of local tumor immunosuppression, which were primarily controlled by either macrophage and regulatory T cell-mediated mechanisms or immunosuppressive cytokines and checkpoints, respectively. None of the immune cell signatures had an independent prognostic value in the present dataset after multiple testing correction. These results suggest a mild, but subgroup-specific infiltration of immune cells in medulloblastoma.

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Section: Discussionsupporting

confidence: 84%

Subgroup-specific immune and stromal microenvironment in medulloblastoma

et al. 2018

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“…PD‐L1 expression in combination with CD8 + T infiltration could be a better predictor of OS. It has also been shown that cytotoxic CD8 + lymphocytes cells infiltrations were associated with a good prognosis in GBM 41 . In this study, immunohistochemical results indicated that both PD‐L1 expression and CD8 + T lymphocytes in GBM were closely related to the prognosis of patients.…”

Section: Discussionsupporting

confidence: 51%

“…It has also been shown that cytotoxic CD8 + lymphocytes cells infiltrations were associated with a good prognosis in GBM. 41 In this study, immunohistochemical results in- 22 In this study, high expressions of EGFR, CSN6, and PD-L1…”

Section: Discussionmentioning

confidence: 67%

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Guo

Lou

et al. 2020

Molecular Carcinogenesis

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Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD‐L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR‐ERK pathway regulates CSN6 for PD‐L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD‐L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD‐L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD‐L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF‐upregulated p‐EGFR, p‐ERK, CSN6, and PD‐L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD‐L1 in EGF‐treated cells. Inhibition of CSN6 by small interfering RNA decreased PD‐L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF‐reduced CHX‐induced CSN6 and PD‐L1 turnover in GBM cells. Furthermore, CSN6‐mediated downregulation of PD‐L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR‐ERK pathway may upregulate CSN6, which may inhibit PD‐L1 degradation and subsequently maintain PD‐L1 stability in GBM.

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“…Although there are several studies carried out to investigate the potential role of IL‐17A in the progression of malignant GBMs, the mechanism of IL‐17A could influence glioma progression remains unclear. In GBM patients, high IL‐17A infiltration is associated with poorer prognosis, suggesting it as a potential prognosis factor . Previously, it has been reported by other group that IL‐17A protein expression is increased in traumatic brain injury group compared with the sham‐operated group in a rat model .…”

Section: Discussionmentioning

confidence: 90%

“…It improves the transition from chronic pancreatitis to pancreatic cancer through the novel REG3β‐JAK2‐STAT3 inflammatory pathway . IL‐17A is frequently observed in many cancers such as ovarian cancer, gastric cancer, and hepatocellular carcinoma, and being reported to associate with a poor clinical outcome in patients with GBM . Higher level of IL‐17A is found in glioma tissues as compared with trauma tissues, however, the role of IL‐17A in migration and invasion of GBM cells is not fully illuminated and the mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 99%

IL‐17A promotes cell migration and invasion of glioblastoma cells via activation of PI3K/AKT signalling pathway

Zheng

Diao

Wang

et al. 2018

J Cellular Molecular Medi

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Glioblastomas (GBMs) are the most common of both benign and malignant primary brain tumours, in which the inflammatory and immunologic abnormalities are involved. Interleukin‐17A (IL‐17A) plays an important role in various inflammatory diseases and cancers. Several recent studies revealed that the expression of IL‐17A was overexpressed in human GBMs tissue. However, the accurate role of IL‐17A in GBMs remains unclear. In this study, we aimed to explore the effect of IL‐17A on cell migration and invasion of GBMs and the mechanism by which the effects occurred. We found that exogenous IL‐17A promoted significantly cell migration and invasion abilities in two GBMs cell lines (U87MG and U251) in a time‐dependent manner. In addition, the protein expressions of PI3K, Akt and MMP‐2/9 were increased in the GBMs cells challenged by IL‐17A. Furthermore, a tight junction protein ZO‐1 was down‐regulated but Twist and Bmi1 were up‐regulated. Treatment with a PI3K inhibitor (LY294002) significantly reduced the abilities of both migration and invasion in U87MG and U251 cells. LY294002 treatment also attenuated the IL‐17A causing increases of protein levels of PI3K, AKT, MMP‐2/9, Twist and the decreases of protein level of ZO‐1 in the U87MG and U251 cells. Taken together, we concluded that IL‐17A promotes the GBM cells migration and invasion via PI3K/AKT signalling pathway. IL‐17A and its related signalling pathways may be potential therapeutic targets for GBM.

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Immune classifications with cytotoxic CD8⁺ and Th17 infiltrates are predictors of clinical prognosis in glioblastoma

Cited by 27 publications

References 31 publications

Subgroup-specific immune and stromal microenvironment in medulloblastoma

Subgroup-specific immune and stromal microenvironment in medulloblastoma

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

IL‐17A promotes cell migration and invasion of glioblastoma cells via activation of PI3K/AKT signalling pathway

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Immune classifications with cytotoxic CD8+ and Th17 infiltrates are predictors of clinical prognosis in glioblastoma

Cited by 27 publications

References 31 publications

Subgroup-specific immune and stromal microenvironment in medulloblastoma

Subgroup-specific immune and stromal microenvironment in medulloblastoma

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

IL‐17A promotes cell migration and invasion of glioblastoma cells via activation of PI3K/AKT signalling pathway

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Immune classifications with cytotoxic CD8⁺ and Th17 infiltrates are predictors of clinical prognosis in glioblastoma