B7-homolog 1 expression by human glioma: a new mechanism of immune evasion

Wilmotte, R; Burkhardt, Karim; Kindler, Vincent; Belkouch, Marie-Claude; Dussex, Géraldine; Tribolet, Nicolas de; Walker, Paul R; Dietrich, Pierre‐Yves

doi:10.1097/00001756-200507130-00010

Cited by 94 publications

(81 citation statements)

References 17 publications

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“…We found GFAP ϩ tumor cells with high PD-L1 expression in the tumor mass (TM) in some of the investigated GBM patients (Table 1; Fig. 1A-F, two GBM patients), consistent with earlier reports (Wilmotte et al, 2005;Yao et al, 2009). A generally high degree of PD-L1 expression (Ͼ10 PD-L1 ϩ cells; Table 1) in the TM significantly correlated with poor prognosis compared with GBM patients with no or lower PD-L1 expression (1-9 PD-L1 ϩ cells) in the TM, shown in Kaplan-Meier survival curves (Fig.…”

Section: Resultssupporting

confidence: 92%

“…Neuronal PD-L1 expression in tumor-adjacent brain tissue is associated with GBM prognosis PD-L1 expression by gliomas limits T-cell activation, helps cells escape immune surveillance, and correlates with high-grade tumors (Wilmotte et al, 2005;Parsa et al, 2007;Yao et al, 2009). However, whether PD-L1 expression by stromal cells in the tumor microenvironment affects GBM outcome is unknown.…”

Section: Resultsmentioning

confidence: 99%

“…This suggested that upregulation of PD-L1 in native brain neurons was a negative feedback signal for downregulation of PD-L1 expression by tumor cells. A defect in such a regulatory pathway might underlie the sustained or upregulated PD-L1 expression in tumor cells that allows tumor cells to evade immune surveillance and correlates with GBM aggressiveness (Wintterle et al, 2003;Wilmotte et al, 2005;Yao et al, 2009). …”

Section: Resultsmentioning

confidence: 99%

“…New targets for successful GBM treatment are urgently needed. PD-L1 is expressed by many cancer cell types (Dong et al, 2002) including glioblastomas (Wilmotte et al, 2005), and could be involved in the induction of apoptosis, resulting in immunosuppression of cancer-antigen specific T cells. Few reports address the role of tissue-specific PD-L1 expression in the tumor microenvironment and its plausible role in cancer suppression.…”

Section: Discussionmentioning

confidence: 99%

“…PD-L1 might confer immunomodulatory properties that help tumors escape from immune surveillance (Dong et al, 2002). Studies have suggested an association between the malignancy grade of astrocytic tumors and tumor cell PD-L1 expression (Wilmotte et al, 2005;Yao et al, 2009), including upregulation of PD-L1 at the growing edge of tumors (Wilmotte et al, 2005;Yao et al, 2009). Constitutive PD-L1 expression is reported to be important for maintaining tolerance against immune-cell attack in several different tissues (Liang et al, 2003;Keir et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 Expression by Neurons Nearby Tumors Indicates Better Prognosis in Glioblastoma Patients

Liu

Carlsson

Ambjørn

et al. 2013

Journal of Neuroscience

124

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Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. In general, tumor growth requires disruption of the tissue microenvironment, yet how this affects glioma progression is unknown. We studied program death-ligand (PD-L)1 in neurons and gliomas in tumors from GBM patients and associated the findings with clinical outcome. Remarkably, we found that upregulation of PD-L1 by neurons in tumor-adjacent brain tissue (TABT) associated positively with GBM patient survival, whereas lack of neuronal PD-L1 expression was associated with high PD-L1 in tumors and unfavorable prognosis. To understand the molecular mechanism of PD-L1 signaling in neurons, we investigated PD-L1 function in cerebellar and cortical neurons and its impact on gliomas. We discovered that neuronal PD-L1-induced caspase-dependent apoptosis of glioma cells. Because interferon (IFN)-␤ induces PD-L1 expression, we studied the functional consequences of neuronal Ifnb gene deletion on PD-L1 signaling and function. IfnbϪ/Ϫ neurons lacked PD-L1 and were defective in inducing glioma cell death; this effect was reversed on PD-L1 gene transfection. Ifnb Ϫ/Ϫ mice with intracerebral isografts survived poorly. Similar to the observations in GBM patients, better survival in wild-type mice was associated with high neuronal PD-L1 in TABT and downregulation of PD-L1 in tumors, which was defective in Ifnb Ϫ/Ϫ mice. Our data indicated that neuronal PD-L1 signaling in brain cells was important for GBM patient survival. Reciprocal PD-L1 regulation in TABT and tumor tissue could be a prognostic biomarker for GBM. Understanding the complex interactions between tumor and adjacent stromal tissue is important in designing targeted GBM therapies.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

PD-L1 Expression by Neurons Nearby Tumors Indicates Better Prognosis in Glioblastoma Patients

Liu

Carlsson

Ambjørn

et al. 2013

Journal of Neuroscience

124

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Assessment of programmed death‐ligand 1 expression and tumor‐associated immune cells in pediatric cancer tissues

Majzner

Simon

Grosso

et al. 2017

Cancer

150

114

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A subset of diagnostic pediatric cancers exhibit PD-L1 expression, whereas a much larger fraction demonstrates infiltration with tumor-associated lymphocytes. PD-L1 expression may be a biomarker for poor outcome in neuroblastoma. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers both at diagnosis and after exposure to chemoradiotherapy. Cancer 2017;123:3807-3815. © 2017 American Cancer Society.

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Treatment with pembrolizumab in programmed death ligand 1–positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE‐028 trial

Reardon

Kim

Frenel

et al. 2021

Cancer

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BACKGROUND: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. METHODS: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). RESULTS: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progressionfree survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

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B7-homolog 1 expression by human glioma: a new mechanism of immune evasion

Cited by 94 publications

References 17 publications

PD-L1 Expression by Neurons Nearby Tumors Indicates Better Prognosis in Glioblastoma Patients

PD-L1 Expression by Neurons Nearby Tumors Indicates Better Prognosis in Glioblastoma Patients

Assessment of programmed death‐ligand 1 expression and tumor‐associated immune cells in pediatric cancer tissues

Treatment with pembrolizumab in programmed death ligand 1–positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE‐028 trial

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