PD‐L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma

Ruf, Melanie; Moch, Holger; Schraml, Peter

doi:10.1002/ijc.30077

Cited by 164 publications

(134 citation statements)

References 37 publications

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“…GLUT1 is an important downstream target of HIF-2α [19,22]. Therefore, a significant correlation between GLUT1 and PD-L1 expression was identified in clear cell renal cell carcinoma [24]. In our study, 91% of patients with GLUT1-positive status had PD-L1 positive status, supporting the HIF-2α–Glut1–PD-L1 pathway identified in a previous study.…”

Section: Discussionsupporting

confidence: 87%

“…Although an objective response was reported in 87% of patients with advanced cHL treated with nivolumab, only 17% of patients exhibited complete responses [25]. Based on the significant correlations of GLUT1 with PD-L1 and PD-L2 in this study and a previous study [24], the HIF-2α–GLUT1–PD-L1 pathway may be efficiently inhibited by GLUT1-specific inhibitor and PD-1–specific inhibitor.…”

Section: Discussionsupporting

confidence: 52%

“…It will be interesting to evaluate the relationship between GLUT1 and PD-L1 because GLUT1 is a well-known target gene of the HIF pathways [19,22,23]. A recent study reported that PD-L1 expression is regulated by GLUT1 in clear cell renal cell carcinoma [24]. An anti–PD-1 monoclonal antibody (nivolumab) has exhibited substantial therapeutic activity and an acceptable safety profile in relapsed or refractory cHL [25].…”

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confidence: 99%

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GLUT1 as a Prognostic Factor for Classical Hodgkin’s Lymphoma: Correlation with PD-L1 and PD-L2 Expression

Koh

Han

Park

et al. 2017

J Pathol Transl Med

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BackgroundGlucose transporter type 1 (GLUT1) expression is linked to glucose metabolism and tissue hypoxia. A recent study reported that GLUT1 was significantly associated with programmed death ligand 1 (PD-L1) as a therapeutic target in relapsed or refractory classical Hodgkin’s lymphoma (cHL). The purpose of this study was to measure the expression of GLUT1 and assess its prognostic significance and potential relationships with PD-L1, programmed death ligand 2 (PD-L2), and programmed death-1 (PD-1) expressions in cHL.MethodsDiagnostic tissues from 125 patients with cHL treated with doxorubicin, bleomycin, vinblastine, and dacarbazine were evaluated retrospectively via immunohistochemical analysis of GLUT1, PD-L1, PD-L2, and PD-1 expression.ResultsThe median follow-up time was 4.83 years (range, 0.08 to 17.33 years). GLUT1, PD-L1, PD-L2, and PD-1 were expressed in 44.8%, 63.2%, 9.6%, and 13.6% of the specimens, respectively. Positive correlations were found between GLUT1 and PD-L1 expression (p = .004) and between GLUT1 and PD-L2 expression (p = .031). GLUT1 expression in Hodgkin/Reed-Sternberg (HRS) cells was not associated with overall survival or event-free survival (EFS) in the entire cohort (p = .299 and p = .143, respectively). A subgroup analysis according to the Ann Arbor stage illustrated that GLUT1 expression in HRS cells was associated with better EFS in advanced-stage disease (p = .029). A multivariate analysis identified GLUT1 as a marginally significant prognostic factor for EFS (p = .068).ConclusionsThis study suggests that GLUT1 expression is associated with better clinical outcomes in advanced-stage cHL and is significantly associated with PD-L1 and PD-L2 expressions.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 99%

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GLUT1 as a Prognostic Factor for Classical Hodgkin’s Lymphoma: Correlation with PD-L1 and PD-L2 Expression

Koh

Han

Park

et al. 2017

J Pathol Transl Med

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“…As discussed above, another mechanism of PD-L1 upregulation is mediated by RT-induced HIF-1α (51, 123). Thus, PD-1/PD-L1 axis may represent an important obstacle to RT-induced tumor rejection, a hypothesis currently being tested in several clinical studies (124).…”

Section: Tgfβ As a Central Regulator Of Rt-induced Tumor Immunogenicitymentioning

confidence: 99%

Barriers to Radiation-Induced In Situ Tumor Vaccination

et al. 2017

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The immunostimulatory properties of radiation therapy (RT) have recently generated widespread interest due to preclinical and clinical evidence that tumor-localized RT can sometimes induce antitumor immune responses mediating regression of non-irradiated metastases (abscopal effect). The ability of RT to activate antitumor T cells explains the synergy of RT with immune checkpoint inhibitors, which has been well documented in mouse tumor models and is supported by observations of more frequent abscopal responses in patients refractory to immunotherapy who receive RT during immunotherapy. However, abscopal responses following RT remain relatively rare in the clinic, and antitumor immune responses are not effectively induced by RT against poorly immunogenic mouse tumors. This suggests that in order to improve the pro-immunogenic effects of RT, it is necessary to identify and overcome the barriers that pre-exist and/or are induced by RT in the tumor microenvironment. On the one hand, RT induces an immunogenic death of cancer cells associated with release of powerful danger signals that are essential to recruit and activate dendritic cells (DCs) and initiate antitumor immune responses. On the other hand, RT can promote the generation of immunosuppressive mediators that hinder DCs activation and impair the function of effector T cells. In this review, we discuss current evidence that several inhibitory pathways are induced and modulated in irradiated tumors. In particular, we will focus on factors that regulate and limit radiation-induced immunogenicity and emphasize current research on actionable targets that could increase the effectiveness of radiation-induced in situ tumor vaccination.

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“…Specifically, after the expression and activation of HIF-1α, MDSCs increase their expression of iNOS and arginase-I, leading to the suppression of T cells. Additionally, HIF-1α regulates expression of immune checkpoint molecules, such as programmed death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death ligand 1 and 2 (PD-L1 and PD-L2), CD80 and CD86, on MDSCs, to promote their differentiation into TAMs and their immunosuppressive function [115, 116]. Other mediators, such as high mobility group box 1 (HMGB-1) and peroxisome proliferator-activated receptor gamma (PPAR-γ), have also been reported to regulate MDSCs.…”

Section: Mechanisms Of Activation Of Mdscs In Bone Metastasesmentioning

confidence: 99%

Molecular Regulation of Bone Metastasis Pathogenesis

Yiang

et al. 2018

Cell Physiol Biochem

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Distant metastases are the major cause of mortality in cancer patients. Bone metastases may cause bone fractures, local pain, hypercalcemia, bone marrow aplasia, and spinal cord compression. Therefore, the management of bone metastases is important in cancer treatment. Normal bone remodeling is regulated by osteoprotegerin ligand (OPGL), receptor activator of NF-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and other cytokines. In the tumor microenvironment, tumor cells induce a vicious cycle that promotes osteoblastic and osteolytic lesions. Studies support the idea that distant metastases may occur due to the immunosuppressive function of myeloid-derived suppressor cells (MDSCs). These cells inhibit T cells and natural killer (NK) cells and differentiate into tumor-associating macrophages (TAMs), monocytes, and dendritic cells (DCs). In this review, we summarize studies focusing on the role of MDSCs in bone metastasis and provide a strong foundation for developing anticancer immune treatments and anticancer therapies, in general.

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PD‐L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma

Cited by 164 publications

References 37 publications

GLUT1 as a Prognostic Factor for Classical Hodgkin’s Lymphoma: Correlation with PD-L1 and PD-L2 Expression

GLUT1 as a Prognostic Factor for Classical Hodgkin’s Lymphoma: Correlation with PD-L1 and PD-L2 Expression

Barriers to Radiation-Induced In Situ Tumor Vaccination

Molecular Regulation of Bone Metastasis Pathogenesis

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