Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma

Aziz, Mohamed A Abd El; Facciorusso, Antonio; Nayfeh, Tarek; Saadi, Samer; Elnaggar, Mohamed; Cotsoglou, Christian; Sacco, Rodolfo

doi:10.3390/vaccines8040616

Cited by 53 publications

(27 citation statements)

References 92 publications

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“…Additionally, tumor-associated chemokines could drive tumorigenesis through polarization of immune subsets into pro-tumor phenotype or by recruiting T regulatory cells ( Mantovani and Locati, 2013 ). Clinicians are emphasizing immunotherapy as a second-line approach to managing HCC ( Abd El Aziz et al, 2020 ; Federico et al, 2020 ). Scholars have also tested several immune checkpoint blockers (ICBs) such as programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in clinical trials ( Lee et al, 2020 ; Pinter et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Zhang

Wei

Fan

et al. 2021

Front. Cell Dev. Biol.

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Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca2+ -dependent) lectin (CLEC) receptors, essential in innate pattern recognition, have potential regulatory effects on immune cell trafficking and modulatory effects on cancer cell activity. However, information on the expression and prognostic value of CLECs in HCC is scanty. Herein, we explored the potential role of CLECs in HCC based on TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, Metascape, TRRUST, and TIMER databases. Results demonstrated a significantly higher mRNA level of CLEC4A and CLEC4L in HCC tissues than normal liver tissues. Contrarily, we found significantly low CLEC4G/H1/H2/M expression in HCC tissues. The IHC analysis revealed the following: Absence of CLEC4A/J/K/M in normal and liver cancer tissues; high CLEC4C expression in HCC tissues; low expression and zero detection of CLEC4D/E/H1/H2/L in HCC tissues and normal tissues, respectively. And the HepG2 and LX-2 were used to verify the expression level of CLEC4s via qRT-PCR in vitro. Furthermore, the expression of CLEC4H1 (ASGR1) and CLEC4H2 (ASGR2) exhibited a significant relation to clinical stages. However, the expression of CLEC4A, CLEC4D, CLEC4E, CLEC4J (FCER2), CLEC4K (CD207), CLEC4G, CLEC4H1, CLEC4M, and CLEC4H2 decreased with tumor progression. Patients expressing higher CLEC4H1/H2 levels had longer overall survival than patients exhibiting lower expression. Moreover, CLEC4A/D/E/J/K/G/H1/M/H2 had significant down-regulated levels of promoter methylation. The expression level of CLEC4s was correlated with the infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophage cells, neutrophil cells, and dendritic cells. Functional analysis revealed the potential role of CLECL4s in virus infection, including COVID-19. Also, hsa-miR-4278 and hsa-miR-324-5p, two potential miRNA targets of CLEC4s, were uncovered. This article demonstrates that CLEC4 is crucial for the development of HCC and is associated with infiltration of various immune cells, providing evidence for new immunotherapy targets in HCC.

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Section: Introductionmentioning

confidence: 99%

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Zhang

Wei

Fan

et al. 2021

Front. Cell Dev. Biol.

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“…Exhausted T cells have a reduced capacity to produce cytokines, to proliferate, and to kill tumour cells; tumour growth is facilitated by blockade of signalling resulting from interaction of the T-cell receptor (TCR) with the major histocompatibility complex (MHC). Key actionable drivers of immune exhaustion in HCC are the PD1–PDL1 pathway and CTLA4 signalling, and blockade of these pathways (i.e., immune checkpoint inhibition) enhances the immune reaction against the tumour cells [ 32 , 33 ]. (Adapted from Giannini et al 2019 [ 33 ].)…”

Section: Figurementioning

confidence: 99%

Evolving Treatment of Advanced Hepatocellular Carcinoma in the Asia–Pacific Region: A Review and Multidisciplinary Expert Opinion

Ogasawara

Choo

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is the fourth most common driver of cancer-related death globally, with an estimated 72% of cases in Asia. For more than a decade, first-line systemic treatments for advanced or unresectable HCC were limited to the multi-targeted kinase inhibitors sorafenib and, more recently, lenvatinib. Now, treatment options have expanded to include immunotherapy, as exemplified by the immune checkpoint inhibitor (ICI) atezolizumab combined with the antiangiogenic agent bevacizumab. Additional combinations of ICIs with kinase inhibitors, other ICIs, or antiangiogenic agents are under investigation, further supporting the new era of immunotherapy for first-line treatment of advanced or unresectable HCC. We describe this evolving landscape and provide expert opinion on therapeutic best practices in the Asia–Pacific region, where different costs of, and patient access to, treatment are a challenge. With the combination of atezolizumab plus bevacizumab likely to become the clinical standard of care, optimising treatment sequence and ensuring patient access to newer therapies remain priorities. Cost containment and treatment sequencing may be facilitated by characterisation of predictive positive and negative biomarkers. With these considerations in mind, this review and expert opinion focused on advanced HCC in the Asia–Pacific region offers perspectives of multiple stakeholders, including physicians, payer systems, and patients.

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“…In view of inflammatory-based pathogenesis, there has been a growing interest in the application of immunotherapy as a systemic therapy in management of patients with HCC. In 2008, administration of sorafenib, a multi-kinase inhibitor that targets vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and rapidly accelerated fibrosarcoma (RAF) in advanced HCC was demonstrated to improve overall survival (OS) and time to progression (TTP) compared with placebo [7][8][9]. However, even with application of sorafenib as a first-line treatment and lenvatinib, regorafenib, cabozantinib, ramucirumab as second-line treatment options, the disease control rates remain less than 60%, with an objective response rate less than 10% [7,10].…”

Section: Introductionmentioning

confidence: 99%

The Immunology of Hepatocellular Carcinoma

et al. 2021

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Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.

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Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma

Cited by 53 publications

References 92 publications

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Evolving Treatment of Advanced Hepatocellular Carcinoma in the Asia–Pacific Region: A Review and Multidisciplinary Expert Opinion

The Immunology of Hepatocellular Carcinoma

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