Programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: prognostic and therapeutic perspectives

Mocan, Tudor; Spârchez, Zeno; Crăciun, Rareș; Bora, Cristina-Nelida; Leucuţa, Daniel-Corneliu

doi:10.1007/s12094-018-1975-4

Cited by 40 publications

(27 citation statements)

References 67 publications

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“…Patients with positive PD-L1 expression had significantly poorer DFS and overall survival (OS) than PD-L1 negative patients. The median DFS and OS were 14.9 and 29.6 months for PD-L1 positive patients compared with not reached and 59.4 months for PD-L1 negative patients, thus confirming the findings of the prognostic value of PD-1/PDL-1 in HCC [68] . Currently, nivolumab, a monoclonal antibody targeting PD-1, obtained an accelerated FDA approval in view of tumor response and durability for the therapy of HCC patients already treated with sorafenib in the phase 1/2 single-arm CheckMate 040 study [69] .…”

Section: Molecular Targets For the Immunotherapysupporting

confidence: 76%

Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

Zhang¹,

Zhao²

2019

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Hepatocellular carcinoma (HCC) is often associated with pre-existing chronic liver pathologies of different origin infections of hepatitis B virus (HBV) and hepatitis C virus. Clinically, the diagnosis and therapy for HCC are very important for the prognosis of patients. However, current methods for HCC diagnosis and therapy have no an optimal accuracy due to the tumor heterogeneity and the frequent late diagnosis. This review summarizes the new advances in molecular diagnosis and therapy of HCC, based on the recent novel biomarkers and new therapeutic strategies for HCC, including alpha-fetoprotein-L3, glypican-3, heat shock protein 90, dickkopf WNT signaling pathway inhibitor 1, paraoxonase 1, highly up-regulated in liver cancer. Moreover, epigenetic regulation, signal pathway, cellular and molecular targets for the immunotherapy, tumor microenviroment and genome sequencing analysis may serve as the molecular expression signatures in clinical practice. For promising new treatment strategy of HCC, targeting molecular therapy based on the restoration of tumor suppressor genes lost and inhibition of oncogenic genes is attractive. The new clinical trials for other molecular-targeted agents, including pembrolizumab, nivolumab, tivantinib, lenvatinib, cabozantinib, and ramucirumab, are ongoing in clinic. Interestingly, anti-HBV drugs display an amazing therapy for HBV-related HCC. In future, the global determination of more biomarkers may provide new insights into the diagnosis of HCC. More importantly, the diagnostic markers should be used to trace patient's follow-up disease progression, guiding doctors to judge and prescribe drugs for status of an illness, prognosis and other processes.

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Section: Molecular Targets For the Immunotherapysupporting

confidence: 76%

Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

Zhang¹,

Zhao²

2019

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“…Among them, the interaction between programmed cell death-1 (PD-1, also termed CD279) and programmed death-ligand 1 (PD-L1, also termed CD274 and B7-H1) is the primary negative immune regulatory signal, which inhibits the antitumor immune activity of effector cells and mediates tumor immune escape (7)(8)(9)(10). Furthermore, immune checkpoint blockers have recently emerged as a mainstream strategy for the treatment of multiple solid tumors, including liver cancer (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Role and mechanism of programmed death‑ligand�1 in hypoxia‑induced liver cancer immune escape (Review)

et al. 2020

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Immune escape plays a vital role in the development of liver cancer. The interaction between programmed death-ligand 1 (PD-L1) and programmed cell death-1 is a key mediator of cancer immune escape, which leads to the suppression of anticancer immunity and promotion of tumor progression. Hypoxia is a common phenomenon in the tumor microenvironment. Under hypoxic conditions, suppressive immune cells, such as regulatory T cells, myeloid-derived suppressor cells and M2 macrophages, are frequently recruited to tumor tissues to form the immunosuppressive microenvironment in liver cancer. These cells secrete cancer-promoting inflammatory cytokines, which activate the STAT3 and NF-κB signaling pathways. Recent studies have shown that STAT3 is associated with NF-κB and that these transcription factors are often co-activated to regulate tumor proliferation, survival, angiogenesis and invasion. The activation of STAT3 and NF-κB signaling pathways can directly and indirectly induce PD-L1 expression. Therefore, further understanding of the association between hypoxia and PD-L1 may help in the future treatment of liver cancer. The present review summarizes the recent progresses on PD-L1-mediated regulation and facilitation of liver cancer cell immune escape in response to hypoxia. Contents 1. Introduction 2. PD-L1/PD-1 interaction in the immune escape of liver cancer 3. Hypoxia-induced recruitment of immunosuppressive cells and regulation of PD-L1 expression 4. Involvement of STAT3 and NF-κB in the regulation of PD-L1 expression in liver cancer 5. Relevance for clinical practice 6. Conclusions

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“…According to previous reports, the B7 family is associated with HCC aggressiveness, leading to a poor prognosis [15][16][17][18][19]. Some reports have confirmed that the differential expression of PD-L1 (B7-H1) in HCC patients may lead to different prognosis outcomes, and inhibition of the PD-L1 immunomodulatory pathways may contribute to antitumor effects in HCC [20][21][22]. B7-H3 triggers inhibitory signals in effector T cells and promotes the progression of hepatitis B virus (HBV) infection, which may lead to the development of HCC [23].…”

Section: Discussionmentioning

confidence: 94%

Alpha-Fetoprotein Regulates the Expression of Immune-Related Proteins through the NF-κB (P65) Pathway in Hepatocellular Carcinoma Cells

Qiu

Yang

et al. 2020

Journal of Oncology

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Background. The prognosis of patients with hepatocellular carcinoma (HCC) is poor, with 60% to 70% of patients developing recurrence and metastasis within five years of radical resection. Alpha-fetoprotein (AFP) plays a significant role in predicting the recurrence and metastasis of HCC after surgery. However, its role in modulating tumor immunity has not been investigated. Our objective was to examine the effect of AFP on the expression of B7 family and activation of the NF-κB (P65) pathway in HCC. Methods. We generated human hepatoma SMMC-7721 cell lines with or without recombinant AFP transfection (AFPup and control groups). Colony formation assay, Transwell invasion assay, and wound healing assay were used to detect the function of AFP. Liver cancer xenografts were made in BALB/c nude male mice (N = 6 per group). After 28 days of inoculation, the expression of immune genes in the HCC tissues, including PD-L (B7-H1), B7-H3, B7-H4, and P65, was evaluated by quantitative real-time PCR (qPCR) and western blot. In addition, immunofluorescence was used to determine the subcellular localization of the P65 protein, a key factor in the NF-κB pathway. An online HCC patients’ dataset was also used to detect the connection between AFP and P65. Results. Overexpression of AFP could enhance proliferation, invasion, and migration of HCC cells. Both qPCR and western blot results demonstrated that the expressions of PD-L1, B7-H4, and P65 were significantly higher in the AFP group compared to the controls (P<0.05). Immunofluorescence results indicated that the majority of the P65 protein was located in the cytoplasm in the control group but was translocated to the nucleus in the AFPup group. The Spearman correlation coefficient confirms that AFP has a positive correlation with P65 in HCC patients (R = 0.33, P=0.05). Conclusion. AFP could enhance proliferation, invasion, and migration in HCC cells. The upregulation of AFP would increase the PD-L1 and B7-H4 mRNA and protein expression in HCC tissues through the upregulation and activation of the P65 protein.

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Programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: prognostic and therapeutic perspectives

Cited by 40 publications

References 67 publications

Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

Molecular diagnosis and therapy of hepatocellular carcinoma: achievements and challenges

Role and mechanism of programmed death‑ligand�1 in hypoxia‑induced liver cancer immune escape (Review)

Alpha-Fetoprotein Regulates the Expression of Immune-Related Proteins through the NF-κB (P65) Pathway in Hepatocellular Carcinoma Cells

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