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

Liu, Yawei; Carlsson, Robert; Ambjørn, Malene; Hasan, Maruf; Badn, Wiaam; Darabi, Anna; Siesjö, Peter; Issazadeh‐Navikas, Shohreh

doi:10.1523/jneurosci.5812-12.2013

Cited by 124 publications

(103 citation statements)

References 31 publications

(8 reference statements)

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“…Patients with glioblastoma often have high PD-L1 expression, but this does not correlate with levels of TILs observed in the tumors (Berghoff et al, 2014). Also, PD-L1 expression on neurons has been shown to, through an unknown, but immune-independent mechanism, kill glioblastoma cells (Liu et al, 2013), and PD-L1 on cancer cells mediated killing of T cells in vitro , which occurred independently of PD-1 (Dong et al, 2002). We considered the possibility that PD-L1 has a function beyond negatively signaling to T cells via PD-1.…”

Section: Resultsmentioning

confidence: 99%

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

Chang

Qiu

O’Sullivan

et al. 2015

Cell

2,341

2,206

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Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic ‘regressor’ tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumors, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.

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Section: Resultsmentioning

confidence: 99%

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

Chang

Qiu

O’Sullivan

et al. 2015

Cell

2,341

2,206

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“…However, the results have been inconsistent. Liu et al [18] were the first to report that PD-L1 expression is a negative prognosticator for survival based on a very small series of 17 GBM cases. In a retrospective study by Berghoff et al [14], who investigated PD-L1 expression in 563 GBMs and its correlation with patient outcome, the presence of diffuse/fibrillary PD-L1 expression was not associated with survival time in a cohort of 117 specimens of newly diagnosed GBM.…”

Section: Pd-l1 Expression and Prognosis Value In Gliomasmentioning

confidence: 99%

Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy

et al. 2017

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Gliomas are the most common type of primary brain tumor in adults. High-grade neoplasms are associated with poor prognoses, whereas low-grade neoplasms are associated with 5-year overall survival rates of approximately 85%. Despite considerable progress in treatment modalities, the outcomes remain dismal. As is the case with many other tumors, gliomas express or secrete several immunosuppressive molecules that regulate immune cell function. Programmed death-ligand 1 (PD-L1) is a coinhibitory ligand that is predominantly expressed by tumor cells. The binding of PD-L1 to its receptor PD-1 has been demonstrated to induce an immune escape mechanism and to play a critical role in tumor initiation and development. Encouraging results following the blockade of the PD-1/PD-L1 pathway have validated PD-L1 or PD-1 as a target for cancer immunotherapy. Studies have reported that the PD-1/PD-L1 pathway plays a key role in glioma progression and in the efficacy of immunotherapies. Thus, progress in research into PD-L1 will enable us to develop a more effective and individualized immunotherapeutic strategy for gliomas. In this paper, we review PD-L1 expression, PD-L1-mediated immunosuppressive mechanisms, and the clinical applications of PD-1/PD-L1 inhibitors in gliomas. Potential treatment strategies and the challenges that may occur during the clinical development of these agents for gliomas are also reviewed.

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“…PD-1 binds to PD-L1 and PD-L2, expressed on surface of tumor cells 50, 63 , tumor-associated macrophages 33 , vascular endothelial cells 64 and some neurons of the tumor microenvironment 65 . Particularly, PD-L1 has been found to have increased expression in GBM patients 45 .…”

Section: Immunotherapy Approachesmentioning

confidence: 99%

Recent advances and future of immunotherapy for glioblastoma

Kamran

Calinescu

Candolfi

et al. 2016

Expert Opinion on Biological Therapy

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Introduction Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. Areas covered Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. Expert opinion Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.

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

Cited by 124 publications

References 31 publications

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy

Recent advances and future of immunotherapy for glioblastoma

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