Intrahepatic PD-1/PD-L1 Up-regulation Closely Correlates with Inflammation and Virus Replication in Patients with Chronic HBV Infection

Xie, Zhiqin; Chen, Yongwen; Zhao, Songtao; Yang, Zhiqing; Yao, Xiaohong; Guo, Sheng; Yang, Chengying; Lei, Fei; Zeng, Xi; Ni, Bing; Wu, Yuzhang

doi:10.1080/08820130903062210

Cited by 48 publications

(43 citation statements)

References 28 publications

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“…However, no significant relationships were found between PD-1/PD-L1 expression and gender, age, number of tumors, HBV DNA load, AFP level or stage of liver function. Although several publications demonstrated that PD-1/PD-L1 expression levels correlated with the HBV DNA titers [30], [31], we did not find any correlations in the present study regarding HCC patients with chronic HBV infection. Besides monocytes, PD-L1 is also expressed in dendritic cells and our previous investigations also revealed a good correlation for PD-L1 expression between these two kinds of cells [23].…”

Section: Discussioncontrasting

confidence: 99%

Upregulation of Circulating PD-L1/PD-1 Is Associated with Poor Post-Cryoablation Prognosis in Patients with HBV-Related Hepatocellular Carcinoma

et al. 2011

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BackgroundThe programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association between circulating PD-L1/PD-1 and prognosis after cryoablation in patients with HBV-related hepatocellular carcinoma (HCC).Methodology/Principal FindingsIn the present study, 141 HBV-related HCC patients were enrolled and of those 109 patients received cryoablation. Circulating PD-L1/PD-1 expression was tested by flow cytometry, and 23 patients were simultaneously evaluated for intratumoral PD-L1 expression by immunohistochemical staining. Circulating PD-1/PD-L1 expression was associated with severity of diseases in patients with HCC, and the circulating PD-L1 expression was closely correlated with intratumoral PD-L1 expression. Of the clinical parameters, PD-1/PD-L1 expression was associated with tumor size, blood vessel invasion and BCLC staging. Moreover, PD-1/PD-L1 expression dropped after cryoablation while being elevated at the time of tumor recurrence. Patients with higher expression of circulating PD-L1, as well as circulating PD-1, had a significantly shorter overall survival and tumor-free survival than those with lower expression. Multivariate analysis confirmed that circulating PD-L1 could serve as an independent predictor of overall survival and tumor-recurrence survival in HCC patients after cryoablation.Conclusions/SignificanceUpregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma.

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Section: Discussioncontrasting

confidence: 99%

Upregulation of Circulating PD-L1/PD-1 Is Associated with Poor Post-Cryoablation Prognosis in Patients with HBV-Related Hepatocellular Carcinoma

et al. 2011

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“…39 In this study, we analyzed the correlation between PD-1 expression level on CD4 þ T cells in peripheral blood and serum ALT level in the different phases of chronic HBV infection. Results showed that both the percentage of PD-1-positive CD4 þ T cells and the MFI of PD-1 expression on CD4 þ T cells were not correlated with serum ALT level in each phase of chronic HBV infection (Figure 4).…”

Section: Pd-1 Expression Level On Cd4mentioning

confidence: 99%

HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients

Sun

Jin

et al. 2012

Laboratory Investigation

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Hyper-expression of programmed death-1 (PD-1) is a hallmark of exhausted T cells. In chronic hepatitis-B virus (HBV)-infected patients, PD-1 upregulation on T cells was often observed. The mechanism of it has not been fully understood. In this study, we examined the dynamic changes of PD-1 expression on T cells during the natural history of chronic HBV infection and explored the signaling pathway of PD-1 upregulation by the hepatitis-B core antigen (HBcAg). Sixty-seven chronic HBV-infected patients were categorized into an immune tolerance group, an immune clearance group and an inactive virus carrier group, and 20 healthy volunteers were chosen as normal control group. Peripheral blood mononuclear cells from patients and healthy volunteers, and T lymphocytes from healthy volunteers were separated. Results showed that the PD-1 expression level on CD4 þ T cells in every phase of chronic HBV infection was significantly higher than that in healthy volunteers, whereas such effects were not observed on CD8 þ T cells. In the immune clearance phase, a positive correlation was found between serum HBV DNA level and the PD-1 expression level on CD4 þ T cells. In all phases, no correlation was shown between serum alanine amino transferase (ALT) level and PD-1 expression level. Phosphorylation of JNK, ERK and AKT was induced by HBcAg, and inhibitors of JNK, ERK and PI3K/AKT significantly decreased the HBcAg-induced PD-1 upregulation on CD4 þ T cells. In conclusion, the PD-1 expression level on CD4 þ T cells was upregulated in every phase of chronic HBV infection, which was induced by HBcAg through JNK, ERK and PI3K/AKT signaling pathways.

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“…15,16 Increased PD L1 expression may allow viruses to avoid immune surveillance. 17 Recently, two groups showed that therapy directed against PD L1 can cause a strong anti-tumor response in a wide variety of metastastic cancers. These manuscripts also documented that cancers that did respond to the anti-PD L1 therapy showed a strong CD8 T-cell presence in the untreated tumor with concomitant high PD L1 expression as seen by immunohistochemistry.…”

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confidence: 99%

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

et al. 2015

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Programmed death ligand 1 (PD L1) expression can reduce the immune response in both infectious diseases and cancers. We thus examined PD L1 expression in cervical intraepithelial neoplasias (CINs) and cancers since they each reflect infection by human papillomavirus (HPV). PD L1 protein was not evident by immunohistochemistry in histologically normal cervical epithelia (0/55) even when adjacent to CIN or cancer. PD L1 expression was much increased in CINs (20/21 = 95%) and cervical squamous cell cancer (56/70 = 80%) and localized to the dysplastic/neoplastic squamous cells and mononuclear cells, respectively. There was also a significant increase (each Po0.001) in PD L1 detection in mononuclear cells when comparing cervical squamous cell cancers to endometrial (22/115 = 19%) and ovarian adenocarcinomas (5/40 = 13%). Co-expression analyses showed that the primary inflammatory cell that contained PD L1 was the CD8+ lymphocyte that strongly concentrated around the dysplastic CIN cells and nests of invasive squamous cancer cells. These data show that PD L1 is a solid biomarker of productive HPV infection of the cervix and that it is significantly upregulated in both the carcinoma and surrounding inflammatory cells in cervical cancer when compared with other gynecologic malignancies. This suggests that anti-PD L1 therapy may have a role in the treatment of cervical cancer.

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Intrahepatic PD-1/PD-L1 Up-regulation Closely Correlates with Inflammation and Virus Replication in Patients with Chronic HBV Infection

Cited by 48 publications

References 28 publications

Upregulation of Circulating PD-L1/PD-1 Is Associated with Poor Post-Cryoablation Prognosis in Patients with HBV-Related Hepatocellular Carcinoma

Upregulation of Circulating PD-L1/PD-1 Is Associated with Poor Post-Cryoablation Prognosis in Patients with HBV-Related Hepatocellular Carcinoma

HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

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