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Vaccines
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The Immunology of Hepatocellular Carcinoma: Towards the Future of Immunotherapy
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The Immunology of Hepatocellular Carcinoma: Towards the Future of Immunotherapy

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Cancer Vaccines and Immunotherapy".

Deadline for manuscript submissions: closed (1 March 2022) | Viewed by 25110

Special Issue Editors

Dr. Valerie Chew

E-Mail Website
Guest Editor
Duke-NUS Medical School Singapore, Singapore City, Singapore
Interests: immune microenvironment; hepatocellular carcinoma; tumour immunology; immunotherapy
Dr. Diamantis I. Tsilimigras

E-Mail Website
Guest Editor
Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, 395 W. 12th Ave., Columbus, OH 43210, USA
Interests: hepatocellular carcinoma; intrahepatic cholangiocarcinoma; liver; pancreas; surgery; biology; immunology; tumor microenvironment; surgical oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide, ranking second highest for cancer-related mortality in men. Despite years of effort in prevention and treatment of HCC, high recurrence rate and detection of HCC at advanced stages, especially in developing countries, remain as major hurdles for reducing its mortality rates. Furthermore, with increasing incidence of fatty-liver related conditions such as Nonalcoholic fatty liver disease (NAFLD) as well as lack of effective systemic therapy for advanced HCC, HCC remains a very challenging and complex cancer to treat.

HCC derives mostly from a background of chronic inflammation due to chronic hepatitis infection or all liver injuries, which often leads to cirrhosis of the liver prior to cancer development. The complex aetiologies and chronic inflammatory liver diseases leading to HCC making the tumour highly heterogeneous in nature hence render most targeted therapies less effective in HCC. Recently, immunotherapeutic strategies have been evaluated in HCC, with some degree of success. Particularly, the immune checkpoint blockade (ICB) using anti-PD-1 monoclonal antibodies, which have shown promising outcome (~20% overall response rate) in early phases clinical trials. Despite the initial enthusiasm, treatment benefit is only appreciated in a modest proportion of patients and considerable therapy-induced immune-related adverse events (irAEs).

The current field of immunotherapy ushered towards combination strategies. Among which, the recent success of IMbrave150 phase III trial using a combination of atezolizumab (anti-PD-L1 antibody) and bevacizumab (anti-VEGF antibody) in patients with advanced HCC would likely change the treatment landscapes for advanced HCC in the future. Despite that, the rationale and design of combination immunotherapy requires deeper understanding into the immunology, the tumour microenvironment as well as general biological processes of HCC in response to immunotherapy.

Critical information and assessment are needed to advance the research into better and more effective immunotherapeutic strategies in HCC. Hence, this Special Issue “The immunology of Hepatocellular Carcinoma: towards the future of immunotherapy” will focus on deeper understanding of the basis of immune circuits in HCC with the special focus on its immune landscapes and on the solid rationale in designing combination immunotherapy strategies with enhanced efficacy as well as tolerable and manageable irAEs.

Dr. Valerie Chew
Dr. Diamantis I. Tsilimigras
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Immune microenvironment
  • tumour immunology
  • hepatocellular carcinoma
  • immunotherapy
  • chronic hepatitis infection
  • cancer vaccines
  • chronic liver inflammation
  • non-alcoholic fatty liver disease

Published Papers (5 papers)

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Review

20 pages, 1028 KiB  
Review
The Immunology of Hepatocellular Carcinoma
by Gbemisola Lawal, Yao Xiao, Amir A. Rahnemai-Azar, Diamantis I. Tsilimigras, Ming Kuang, Anargyros Bakopoulos and Timothy M. Pawlik
Vaccines 2021, 9(10), 1184; https://doi.org/10.3390/vaccines9101184 - 15 Oct 2021
Cited by 41 | Viewed by 4891
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Immunology of Hepatocellular Carcinoma: Towards the Future of Immunotherapy)
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18 pages, 15104 KiB  
Review
The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment
by Patrizia Leone, Antonio Giovanni Solimando, Rossella Fasano, Antonella Argentiero, Eleonora Malerba, Alessio Buonavoglia, Luigi Giovanni Lupo, Valli De Re, Nicola Silvestris and Vito Racanelli
Vaccines 2021, 9(5), 532; https://doi.org/10.3390/vaccines9050532 - 20 May 2021
Cited by 63 | Viewed by 5692
Abstract
Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization [...] Read more.
Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials. Full article
(This article belongs to the Special Issue The Immunology of Hepatocellular Carcinoma: Towards the Future of Immunotherapy)
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22 pages, 1007 KiB  
Review
The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma
by Oraianthi Fiste, Ioannis Ntanasis-Stathopoulos, Maria Gavriatopoulou, Michalis Liontos, Konstantinos Koutsoukos, Meletios Athanasios Dimopoulos and Flora Zagouri
Vaccines 2021, 9(5), 422; https://doi.org/10.3390/vaccines9050422 - 22 Apr 2021
Cited by 13 | Viewed by 4587
Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of [...] Read more.
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions. Full article
(This article belongs to the Special Issue The Immunology of Hepatocellular Carcinoma: Towards the Future of Immunotherapy)
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19 pages, 1212 KiB  
Review
Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma
by Mohamed A. Abd El Aziz, Antonio Facciorusso, Tarek Nayfeh, Samer Saadi, Mohamed Elnaggar, Christian Cotsoglou and Rodolfo Sacco
Vaccines 2020, 8(4), 616; https://doi.org/10.3390/vaccines8040616 - 19 Oct 2020
Cited by 54 | Viewed by 3811
Abstract
Despite the advances in screening protocols and treatment options, hepatocellular carcinoma (HCC) is still considered to be the most lethal malignancy in patients with liver cirrhosis. Moreover, the survival outcomes after failure of first-line therapy for unresectable HCC is still poor with limited [...] Read more.
Despite the advances in screening protocols and treatment options, hepatocellular carcinoma (HCC) is still considered to be the most lethal malignancy in patients with liver cirrhosis. Moreover, the survival outcomes after failure of first-line therapy for unresectable HCC is still poor with limited therapeutic options. One of these options is immune checkpoint inhibitors. The aim of this study is to comprehensively review the efficacy and safety of immune checkpoint inhibitors for patients with HCC. Full article
(This article belongs to the Special Issue The Immunology of Hepatocellular Carcinoma: Towards the Future of Immunotherapy)
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21 pages, 614 KiB  
Review
Immunotherapy with Checkpoint Inhibitors for Hepatocellular Carcinoma: Where Are We Now?
by Francesco Tovoli, Stefania De Lorenzo and Franco Trevisani
Vaccines 2020, 8(4), 578; https://doi.org/10.3390/vaccines8040578 - 2 Oct 2020
Cited by 17 | Viewed by 4978
Abstract
Immune checkpoint inhibitors (ICIs) are beginning to show promise in the clinical management of hepatocellular carcinoma (HCC). Most recently, the anti-programmed death protein-1 (PD-1) agent atezolizumab combined with bevacizumab demonstrated superiority to sorafenib in a Phase 3 randomised clinical trial in the frontline [...] Read more.
Immune checkpoint inhibitors (ICIs) are beginning to show promise in the clinical management of hepatocellular carcinoma (HCC). Most recently, the anti-programmed death protein-1 (PD-1) agent atezolizumab combined with bevacizumab demonstrated superiority to sorafenib in a Phase 3 randomised clinical trial in the frontline setting. Other ongoing trials of immunotherapy for HCC are exploring different drug combinations, such as a double checkpoint blockade with PD-1 and anti-Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents or with tyrosine kinase inhibitors. Moreover, ICIs are being tested in the adjuvant and neoadjuvant settings trying to resolve long-time unmet needs in HCC. The results of the ongoing trials will be critical to understanding the extent of the therapeutic role of ICIs in the complex and multifaceted clinical scenario of HCC. Still, there are some critical points which need further attention to clarify the best use of ICIs in HCC patients. For instance, the actual eligibility rate of patients in the real-life scenario, the prompt identification and correct management of immune-mediated adverse events, the identification of biomarkers predicting response or resistance, and strategies to prevent the tumour escape from ICI effect. Full article
(This article belongs to the Special Issue The Immunology of Hepatocellular Carcinoma: Towards the Future of Immunotherapy)
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