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

Koh, Young Wha; Han, Jae Ho; Park, Sung Yong; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung

doi:10.4132/jptm.2016.11.03

Cited by 21 publications

(19 citation statements)

References 37 publications

(48 reference statements)

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“…Pin wu et al performed a meta-analysis of solid tumors and showed that PD-L1 overexpression was associated with poor 3-year OS in all studies analyzed, with the exception of one study on melanoma and lung cancer. Interestingly, few studies of the PD-1 and PD-L1 pathway in HL have been performed [47] , [48] . HL usually exhibits diffuse and strong PD-L1 positivity in tumor (RS) cells based on IHC [49] .…”

Section: Discussionmentioning

confidence: 99%

High Serum Level of Soluble Programmed Death Ligand 1 is Associated With a Poor Prognosis in Hodgkin Lymphoma

Guo

Wang

Jin

et al. 2018

Translational Oncology

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Blockade of the programmed cell death 1-programmed cell death ligand 1 pathway is a new and promising therapeutic approach in Hodgkin lymphoma (HL). To our knowledge, the impact of soluble programmed cell death ligand 1 (sPD-L1) serum levels on HL patient prognosis has not yet been investigated. In this study, the prognostic value of sPD-L1 was assessed in patients with HL. We measured serum sPD-L1 levels and identified their prognostic value in 108 newly diagnosed HL patients using an enzyme-linked immunosorbent assay (ELISA). We found higher serum sPD-L1 concentrations in HL patients than in healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 25.1674 ng/ml. The 4-year progression-free survival (PFS) rates for the high-sPD-L1 and low-sPD-L1 groups were 78.8% and 93.3%, respectively. Multivariate survival analysis showed that advanced stage and higher sPD-L1 levels (>25.1674 ng/ml) were independent prognostic factors for shorter PFS. In addition, higher sPD-L1 levels were positively correlated with advanced stage and negatively correlated with peripheral blood monocyte number. The serum sPD-L1 level is an independent prognostic factor for PFS in HL patients and may allow identification of a subgroup of patients who require more intensive therapy and who may benefit from anti-PD-1 agents.

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Section: Discussionmentioning

confidence: 99%

High Serum Level of Soluble Programmed Death Ligand 1 is Associated With a Poor Prognosis in Hodgkin Lymphoma

Guo

Wang

Jin

et al. 2018

Translational Oncology

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“…The presence of hypoxia-response elements (HRE) within the PD-L1 promoter region has highlighted a therapeutically attractive link between hypoxia/angiogenesis and anti-tumor immune suppression, 26 with similar mechanisms being implied in the regulation of PD-L2 expression. 27 …”

Section: Discussionmentioning

confidence: 99%

“…Biologically, elevated PD-L1 expression within tumor cells or the surrounding microenvironment is dynamic as a result of various molecular events including hypoxia 17 and similar correlations have been highlighted for PD-L2. 18 We have previously shown that activation of hypoxia inducible factor 1α (Hif-1α) is a key molecular hallmark in the metastatic progression of PCC/PGL, 19 a disease where constitutive Hif-1α stabilization secondary to mitochondrial dysfunction, termed “pseudo-hypoxia,” is a key pathophysiological trait. 20 …”

Section: Introductionmentioning

confidence: 99%

Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: Relationship with the hypoxic response, immune evasion and malignant behavior

et al. 2017

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The hypoxic response underlies the pathogenesis and malignant behavior of PCC/PGL. Regulation of PD-1 receptor-ligand signaling, a therapeutically actionable driver of the anti-tumor immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL.Tissue microarrays sections including consecutive cases diagnosed between 1983–2011 were stained for PD-L1 and 2, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). We explored the biologic significance of PD ligands expression using gene set enrichment analysis (GSEA) on The Cancer Genome Atlas (TCGA) for PCC/PGL (n = 184).In total, 100 patients, 10% malignant, 64% PCC, 29% familial with median tumor size of 4.7 cm (range 1–14) were included. Median follow-up was 4.7 y. We found PD-L1 expression in 18% of PCC/PGL, which was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. PD-L2 expression (16%) strongly correlated with CI, VI, N and malignant behavior (p < 0.05) and was associated with stronger Hif-1a and CaIX immunolabeling (p < 0.01). PD-L2 was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1–9.2, p = 0.02). GSEA on TGCA samples confirmed enrichment of transcripts involved in hypoxia and anti-cancer immunity.We report for the first time PD ligands expression in PCC/PGL with a distinctive prognostic, clinico-pathologic and immuno-biologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumors.KEY MESSAGEThe molecular mechanisms underlying immune evasion in malignant phaeochromocytomas and paragangliomas (PCC/PGL) are poorly understood. This study demonstrates for the first time a distinctive immune-biologic and prognostic role of programmed death ligands 1 and 2 (PD-L1, PD-L2), two actionable drivers of the anti-cancer immune response. RNA-sequencing of tumor tissues reveals enrichment of transcripts relating to hypoxia and immune-exhaustion to explain the adverse clinical course observed in PD-L2 overexpressing tumors. These findings provide a rationale for the development of anti PD-1 therapies in malignant PCC/PGL.

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“…20,21 As mentioned above, it has been reported that the PD-L1 expression is positively regulated by HIF-1A activation and that HIF-1A-induced GLUT1 expression is related to high PD-L1 expression and EMT induction, which is characterised by E-cadherin suppression and cancer aggressiveness. 42,43 Conversely, PD-L1 expression has been reported to be downregulated by EMT induction, and the high 18 F-FDG-uptake in cancer tissues is negatively related to low E-cadherin expression as one of the EMT phenotypes. 23 Interestingly, the HIF-1A/GLUT1/ EMT axis has been known to regulate PD-L1 expression as well as 18 F-FDG-uptake; 22,28 however, the relationship between PD-L1 expression, FDG-uptake, and the HIF-1A/GLUT1/EMT axis in identical OSCC samples has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic value of 18F-FDG-PET to predict the tumour immune status defined by tumoural PD-L1 and CD8+tumour-infiltrating lymphocytes in oral squamous cell carcinoma

et al. 2020

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BACKGROUND: Lately, immune checkpoint proteins, such as programmed death 1 (PD-1) and its ligand-1 (PD-L1), have garnered attention as a new target in oral squamous cell carcinoma (OSCC). Reportedly, fluoro-D-glucose (FDG)-uptake alteration by anti-PD-1 antibody treatment depicts the response in patients with lung cancer. This study aims to elucidate the correlations between tumour immune status, clinicopathological factors, 18 F-FDG-uptake and cold tumour phenotypes as low PD-L1 expression/low CD8 + tumour-infiltrating lymphocytes (TILs) in OSCC. METHODS: We performed immunohistochemical analysis of PD-L1, hypoxia-inducible factor 1 A (HIF-1A), glucose transporter type 1 (GLUT1), CD8, E-cadherin and Ki-67 on 59 operable OSCC samples. We assessed the correlations between these factors and preoperative 18 F-FDG-uptake, clinicopathological characteristics and prognosis. RESULTS: Low expression of PD-L1 in OSCC correlated with cancer aggressiveness, poor prognosis, high 18 F-FDG-uptake with HIF-1A/GLUT1 and low E-cadherin expression and low CD8. Cold tumour phenotypes as low PD-L1 tumour cells and low stromal CD8 correlated with the poor prognosis, high 18 F-FDG-uptake and E-cadherin suppression. Furthermore, the high level of preoperative 18 F-FDG-uptake in OSCC was an independent predictor of the cold tumour immune status. CONCLUSIONS: 18 F-FDG-uptake is an independent predictor of cold tumour in OSCC. 18 F-FDG-PET imaging could be a promising diagnostic tool to estimate tumour immune status.

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

Cited by 21 publications

References 37 publications

High Serum Level of Soluble Programmed Death Ligand 1 is Associated With a Poor Prognosis in Hodgkin Lymphoma

High Serum Level of Soluble Programmed Death Ligand 1 is Associated With a Poor Prognosis in Hodgkin Lymphoma

Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: Relationship with the hypoxic response, immune evasion and malignant behavior

Diagnostic value of 18F-FDG-PET to predict the tumour immune status defined by tumoural PD-L1 and CD8+tumour-infiltrating lymphocytes in oral squamous cell carcinoma

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