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Wang Y, Zhou H, Ju S, Dong X, Zheng C. The solid tumor microenvironment and related targeting strategies: a concise review. Front Immunol 2025; 16:1563858. [PMID: 40207238 PMCID: PMC11979131 DOI: 10.3389/fimmu.2025.1563858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/12/2025] [Indexed: 04/11/2025] Open
Abstract
The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.
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Affiliation(s)
- Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Huimin Zhou
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Xiangjun Dong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
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2
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Jiang L, Meng Q, Liu L, Li W. A Comprehensive Review on Molecular Mechanisms, Treatments, and Brief Role of Natural Products in Hepatocellular Cancer. Nat Prod Commun 2024; 19. [DOI: 10.1177/1934578x241284873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Most initial liver cancers are hepatocellular carcinomas (HCC), which make up the vast majority of cases. Hepatitis B or C virus infection as well as alcohol consumption is among the key risk factors. The significance of the most intriguing soluble factors as indicators for early diagnosis and as suggested targets for therapy in light of the increasing challenges in precision medicine. The development of HCC is influenced by a complex combination between pro-inflammatory and anti-inflammatory cytokines and their signalling cascades. Recently,researchers are aims to assess the potential of a number of distinct molecular cascade/cascade including cytokines to function as key players with particular underlying etiologies. Increasing our knowledge of the signaling network that links retro differentiation and inflammationmay help us find novel therapeutic targets and develop combined therapies or treatments that work against tumors with a significant degree of heterogeneity. With nursing processes at its center, comprehensive nursing care is a new nursing paradigm that combines the benefits of primary and group nursin g as well as a perfect synthesis of many nursing metrics like nursing philosophy, nursing plan, and nursing quality evaluation. In order to treat patients with serious liver diseases like cancer, it can conduct nursing interventions item by item in accordance with the unique disease conditions of each patient and combine efficient therapeutic approaches with high-quality nursing modes. Dietary natural products, including fruits, vegetables, and spices, may prevent and treat liver cancer by inhibiting tumor growth, protecting the liver, and enhancing chemotherapy.
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Affiliation(s)
- Linlin Jiang
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Qin Meng
- Department of Nursing, Huaian Hospital of Huaian City, Huaian Jiangsu,China
| | - Lixiu Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
| | - Weihang Li
- Interventional Radiology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, China
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Jung YH, Lee DC, Kwon YM, Jang E, Choi G, Kim YH, Kim TH, Kim JH. The Comparative Metabolism of a Novel Hepatocellular Carcinoma Therapeutic Agent, 2,3-Diamino- N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide, in Human and Animal Hepatocytes. Metabolites 2024; 14:425. [PMID: 39195521 DOI: 10.3390/metabo14080425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 08/29/2024] Open
Abstract
[2,3-diamino-N-(4-(benzo[d]thiazol-2-yl)phenyl)propanamide], named as ETN101, is a novel therapeutic agent for hepatocellular carcinoma. In vitro studies examined ETN101 metabolites in human, mouse, rat, dog, and monkey hepatocytes and identified the drug-metabolizing enzymes involved using cDNA-expressed human recombinant cytochrome P450s (CYPs), carboxylesterases (CESs), N-acetyltransferase (NAT) 1, and human liver cytosol. ETN101 showed similar metabolic stability across hepatocytes from five species, with particularly comparable stability in humans, rats, and monkeys. Its half-life was 75.0 min in humans, 68.9 in rats, 73.1 in monkeys, 120.4 in mice, and 112.7 in dogs. Thirty-four ETN101 metabolites, including the major metabolite M1, were identified using liquid chromatography-high-resolution mass spectrometry. ETN101 was primarily metabolized to M1 and CYP1A2 is exclusively responsible for M1 metabolism. Both NAT1 and NAT2 were responsible for the N-acetylation of M1 to M2. ETN101 remained stable in human CESs. In conclusion, this study provides comprehensive insights into the metabolic characteristics of ETN101, valuable for its toxicological and clinical development.
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Affiliation(s)
- Young-Heun Jung
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Dong-Cheol Lee
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Ye-Min Kwon
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Eunbee Jang
- Etnova Therapeutics, Suwon 16648, Republic of Korea
| | - Garam Choi
- Etnova Therapeutics, Suwon 16648, Republic of Korea
| | | | - Tae Hwan Kim
- College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea
| | - Ju-Hyun Kim
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
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4
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Chamseddine S, LaPelusa M, Carter K, Nguyen V, Mohamed YI, Sakr Y, Rojas-Hernandez CM, Hatia RI, Hassan M, Goss JA, Elsayes KM, Rashid A, Sun R, Tran Cao HS, Amin HM, Kaseb AO. Severe febrile neutropenia and pancytopenia in a patient with advanced hepatocellular carcinoma treated with atezolizumab and bevacizumab: a case report. J Gastrointest Oncol 2024; 15:1324-1330. [PMID: 38989410 PMCID: PMC11231852 DOI: 10.21037/jgo-24-290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/31/2024] [Indexed: 07/12/2024] Open
Abstract
Background Immune checkpoint inhibitors (ICIs), agents that stimulate T-cell function, have become the standard first-line treatment for unresectable hepatocellular carcinoma (HCC). However, they may also cause immune-related adverse events (irAEs), which are rare and have not been extensively reported. Here, we describe a case of severe febrile neutropenia and pancytopenia after atezolizumab plus bevacizumab (atezo/bev) therapy and its treatment course. Case Description The combination of atezo/bev was initiated as the first-line treatment for a man in his early 50s, who was diagnosed with unresectable HCC. The first treatment cycle was administered in the outpatient setting, and the patient developed a fever of 39.0 ℃ 10 days after therapy initiation. He presented 5 days later with persistent fever as well as a headache, vomiting, chills, generalized pain, fatigue, mild abdominal discomfort, and a burning rash present on his neck and face. Complete blood counts showed severe neutropenia [absolute neutrophil count (ANC) of 90 cells/µL], leukopenia [white blood cell (WBC) count 500 cells/µL], thrombocytopenia [platelet count (PC) 18,000 cells/µL], and mild anemia (hemoglobin level 12.6 gm/dL). Imaging findings showed colitis on computed tomography (CT). Atezo/bev therapy was discontinued. Treatment plan constituted of cefepime and filgrastim, a recombinant form of the naturally occurring granulocyte colony-stimulating factor (G-CSF) for febrile neutropenia, metronidazole for colitis, and intravenous methylprednisolone for immune-related toxicities. The patient fully recovered after 4 days of admission. Conclusions In conclusion, we observed temporary severe febrile neutropenia and pancytopenia during systemic immunotherapy in a patient with unresectable HCC. Healthcare providers should consider hematological irAEs (hem-irAEs) in patients after the administration of ICIs.
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Affiliation(s)
- Shadi Chamseddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael LaPelusa
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kristen Carter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Van Nguyen
- Department of Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yehia I. Mohamed
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yara Sakr
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Rikita I. Hatia
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manal Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John A. Goss
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
| | - Khaled M. Elsayes
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Asif Rashid
- Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ryan Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hop Sanderson Tran Cao
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hesham M. Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ahmed O. Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Ruli TM, Pollack ED, Lodh A, Evers CD, Price CA, Shoreibah M. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma and Their Hepatic-Related Side Effects: A Review. Cancers (Basel) 2024; 16:2042. [PMID: 38893164 PMCID: PMC11171072 DOI: 10.3390/cancers16112042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Primary liver cancer is one of the leading causes of cancer mortality worldwide, with hepatocellular carcinoma (HCC) being the most prevalent type of liver cancer. The prognosis of patients with advanced, unresectable HCC has historically been poor. However, with the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs), there is reason for optimism. Nevertheless, ICIs do not come without risk, especially when administered in patients with HCC, given their potential underlying poor hepatic reserve. Given their novelty in the management of HCC, there are few studies to date specifically investigating ICI-related side effects on the liver in patients with underlying HCC. This review will serve as a guide for clinicians on ICIs' role in the management of HCC and their potential side effect profile. There will be a discussion on ICI-related hepatotoxicity, the potential for hepatitis B and C reactivation with ICI use, the potential for the development of autoimmune hepatitis with ICI use, and the risk of gastrointestinal bleeding with ICI use. As ICIs become more commonplace as a treatment option in patients with advanced HCC, it is imperative that clinicians not only understand the mechanism of action of such agents but also understand and are able to identify hepatic-related side effects.
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Affiliation(s)
- Thomas M. Ruli
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Ethan D. Pollack
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Atul Lodh
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Charles D. Evers
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Christopher A. Price
- Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (E.D.P.); (A.L.); (C.A.P.)
| | - Mohamed Shoreibah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA;
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Dawood ZS, Brown ZJ, Alaimo L, Lima HA, Shaikh C, Katayama ES, Munir MM, Moazzam Z, Endo Y, Woldesenbet S, Pawlik TM. Comparison of tumor response and outcomes of patients with hepatocellular carcinoma after multimodal treatment including immune checkpoint inhibitors - a systematic review and meta-analysis. HPB (Oxford) 2024; 26:618-629. [PMID: 38369433 DOI: 10.1016/j.hpb.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 01/13/2024] [Accepted: 02/06/2024] [Indexed: 02/20/2024]
Abstract
BACKGROUND The efficacy of immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs), trans-arterial chemoembolization (TACE), and radiotherapy to treat hepatocellular carcinoma (HCC) has not been well-defined. We performed a meta-analysis to characterize tumor response and survival associated with multimodal treatment of HCC. METHODS PubMed, Embase, Medline, Scopus, and CINAHL databases were searched (1990-2022). Random-effect meta-analysis was conducted to compare efficacy of treatment modalities. Odds ratios (OR) and standardized mean difference (SMD) were reported. RESULTS Thirty studies (4170 patients) met inclusion criteria. Triple therapy regimen (ICI + TKI + TACE) had the highest overall disease control rate (DCR) (87%, 95% CI 83-91), while ICI + radiotherapy had the highest objective response rate (ORR) (72%, 95% CI 54%-89%). Triple therapy had a higher DCR than ICI + TACE (OR 4.49, 95% CI 2.09-9.63), ICI + TKI (OR 3.08, 95% CI 1.63-5.82), and TKI + TACE (OR 2.90, 95% CI 1.61-5.20). Triple therapy demonstrated improved overall survival versus ICI + TKI (SMD 0.72, 95% CI 0.37-1.07) and TKI + TACE (SMD 1.13, 95% CI 0.70-1.48) (both p < 0.05). Triple therapy had a greater incidence of adverse events (AEs) compared with ICI + TKI (OR 0.59, 95% CI 0.29-0.91; p = 0.02), but no difference in AEs versus ICI + TACE or TKI + TACE (both p > 0.05). CONCLUSION The combination of ICIs, TKIs and TACE demonstrated superior tumor response and survival and should be considered for select patients with advanced HCC.
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Affiliation(s)
- Zaiba S Dawood
- Medical College, The Aga Khan University Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Zachary J Brown
- Department of Surgery, New York University Long Island School of Medicine, Mineola, NY, USA
| | - Laura Alaimo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Henrique A Lima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Chanza Shaikh
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Erryk S Katayama
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Muhammad M Munir
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Zorays Moazzam
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Yutaka Endo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Selamawit Woldesenbet
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.
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Akbulut Z, Aru B, Aydın F, Yanıkkaya Demirel G. Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Front Immunol 2024; 15:1379622. [PMID: 38638433 PMCID: PMC11024234 DOI: 10.3389/fimmu.2024.1379622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/18/2024] [Indexed: 04/20/2024] Open
Abstract
Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.
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Affiliation(s)
- Zeynep Akbulut
- Cancer and Stem Cell Research Center, Maltepe University, Istanbul, Türkiye
- Department of Medical Biology and Genetics, Faculty of Medicine, Maltepe University, Istanbul, Türkiye
| | - Başak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Furkan Aydın
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
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Keawvilai P, Kueanjinda P, Klomsing J, Palaga T. Coculturing liver cancer cells and monocytes in spheroids conditions monocytes to adopt tumor-associated macrophage phenotypes that favor tumor growth via cholesterol metabolism. J Leukoc Biol 2024; 115:344-357. [PMID: 37742062 DOI: 10.1093/jleuko/qiad114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 09/05/2023] [Accepted: 09/08/2023] [Indexed: 09/25/2023] Open
Abstract
Tumor-infiltrating immune cells and their crosstalk with cancer cells in the tumor microenvironment (TME) play a crucial role in shaping tumor progression and response to therapy. We utilized 3-dimensional liver cancer spheroids incorporating human primary monocytes to investigate the crosstalk between tumor-associated macrophages (TAMs) and Hepatocellular carcinoma (HCC) cells, HepG2 and PLC/PRF/5. Using multiplexed gene expression panels, the critical pathways involved in shaping primary human monocytes to adopt TAMs phenotypes were identified. The specific inhibitor for an identified pathway was used to explore its involvement in polarization of TAMs. In the cocultured spheroids comprising the human HCC cell lines, the infiltrating monocytes resembled protumor M2-like macrophage phenotypes. Gene expression panels of the infiltrating monocytes demonstrated that the upregulated genes were enriched in the cholesterol metabolism pathway. Cholesterol metabolism-related genes were upregulated together with the nuclear receptors, PPARG and LXR. When lysosomal acid lipase (LAL), the key enzyme necessary for the hydrolysis of lipoprotein, was inhibited, infiltrating monocytes in 3-dimensional spheroid coculture showed significantly decreased M2 marker and lipid uptake receptor expression as well as increased cellular lipid content, which indicated that cholesterol metabolism was important for conditioning the TAMs. Moreover, LAL inhibition reduced the spheroid growth and invasiveness of HCC cell lines. Small interfering RNA-mediated LAL silencing in monocytes yielded similar results upon spheroid coculture. These data indicated that liver cancer cells and infiltrating monocytes participate in crosstalk via cholesterol metabolism to condition monocytes toward TAMs, which favors tumor growth and survival, thereby promoting liver cancer progression.
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Affiliation(s)
- Pornlapat Keawvilai
- Graduate Program in Biotechnology, Faculty of Science, Chulalongkorn University, Phyathai Road, Pathumwan, Bangkok 10330, Thailand
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Phyathai Road, Pathumwan, Bangkok 10330, Thailand
| | - Patipark Kueanjinda
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Phyathai Road, Pathumwan, Bangkok 10330, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Rama 4 Road, Pathumwan, Bangkok 10330, Thailand
| | - Jeerameth Klomsing
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Phyathai Road, Pathumwan, Bangkok 10330, Thailand
| | - Tanapat Palaga
- Center of Excellence in Immunology and Immune-Mediated Diseases, Chulalongkorn University, Phyathai Road, Pathumwan, Bangkok 10330, Thailand
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Phyathai Road, Pathumwan, Bangkok 10330, Thailand
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Wang Y, Ju S, Zhou H, Bai Y, Zhou C, Liu J, Dong X, Zheng C. Synergistic Effects of Nanoscale CaO 2 Combined with PD-1 Inhibitors in the Treatment of Hepatocellular Carcinoma: A Promising Combination. Int J Nanomedicine 2024; 19:137-154. [PMID: 38196507 PMCID: PMC10775804 DOI: 10.2147/ijn.s440387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 12/19/2023] [Indexed: 01/11/2024] Open
Abstract
Purpose To explore the effect of calcium peroxide nanoparticles (CaO2 NPs) combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of liver cancer and its related mechanism. Methods Hepa1-6 cells were cultured to construct the Hepa1-6 mouse liver cancer model. In vivo mechanism study, a unilateral tumor model was established. Eighteen tumor-bearing mice were randomly divided into the control group (intra-tumoral injection of PBS solution) and the experimental group (intra-tumoral injection of CaO2 NPs). A hypoxic probe, pH probe, and micro-CT were used to evaluate the effect of CaO2 NPs on improving hypoxia, neutralizing acidity, and inducing calcium overload within the tumor. To study the effect of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors, the bilateral tumor model was established. Forty tumor-bearing mice were randomly divided into the control group (intra-tumoral/intra-peritoneal injection of PBS solution), CaO2 NPs group (intra-tumoral injection of CaO2 NPs), PD-1 group (intra-peritoneal injection of PD-1 inhibitor), and the combination group (intra-tumoral injection of CaO2 NPs and intra-peritoneal injection of PD-1 inhibitors). The administered side was recorded as the proximal tumor. Tumor volume and body weight were measured every 2 days after treatment. On day 8, serum and tumor samples were collected. The immune factors in serum (Interferon-γ (IFN-γ), Tumour necrosis factor-α (TNF-α), Interleukin-2 (IL-2), and Interleukin-10 (IL-10)) and tumor tissue (IFN-γ and TNF-α) were detected by ELISA. H&E staining was used to detect tumor necrosis. Immunohistochemical staining was used to detect the amount of CD4+ and CD8+ T cells within the tumor. By analyzing the tumor volume, pathological indexes, and immune-related indexes, the effects of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors were evaluated, and they mediated immunomodulatory effects (including local and systemic immunity), and their effects on tumor burden were studied. In addition, a unilateral tumor model was established to study the effect of CaO2 NPs combined with PD-1 inhibitors on survival time. Results The results of in vivo mechanism study showed that CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors. The results of the study on the effect of CaO2 NPs combined with PD-1 inhibitor on proximal and distal tumors showed that, compared with the other three groups, the bilateral tumor burden of the combination group was significantly reduced, the intra-tumoral infiltration of CD8+ and CD4+ T cells were significantly increased, the secretion of anti-tumor immune factors in tumor and serum was increased, and the secretion of pro-tumor immune factors was decreased. Mice in the combination group showed the longest survival compared with the other groups. Conclusion CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors, so as to reduce tumor burden and realize an immunosuppressive tumor transformation to a hot tumor, and play a synergistic role with PD-1 inhibitors in anti-liver cancer.
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Affiliation(s)
- Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Huimin Zhou
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Xiangjun Dong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
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Villalobos A, Dabbous HH, Little O, Gbolahan OB, Akce M, Lilly MA, Bercu Z, Kokabi N. Safety and Efficacy of Concurrent Atezolizumab/Bevacizumab or Nivolumab Combination Therapy with Yttrium-90 Radioembolization of Advanced Unresectable Hepatocellular Carcinoma. Curr Oncol 2023; 30:10100-10110. [PMID: 38132368 PMCID: PMC10742675 DOI: 10.3390/curroncol30120734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 11/06/2023] [Accepted: 11/11/2023] [Indexed: 12/23/2023] Open
Abstract
To evaluate the safety and efficacy of combining yttrium-90 radioembolization (Y90-RE) with immune checkpoint inhibitor therapy, consecutive advanced unresectable hepatocellular carcinoma (HCC) patients treated between 2016 and 2022 with atezolizumab/bevacizumab or nivolumab within three-months pre- and post-Y90-RE were retrospectively evaluated. Tumor response and treatment-related clinical/laboratory adverse events (AE) were assessed at 1 and 6 months, as well as differences in clinical and laboratory variables and median overall survival (OS) from initial treatment (whether it was Y90-RE or systemic therapy) between the two cohorts. A total of 19 patients (10 atezolizumab/bevacizumab; 9 nivolumab), comprising 84% males with median age 69 years, met the inclusion criteria. Compared to the atezolizumab/bevacizumab group, there were less males (100% vs. 67%; p = 0.02) and more ECOG ≥ 2 patients in the nivolumab group (0% vs. 33%; p = 0.02). Baseline characteristics or incidence of 6-month post-treatment any-grade AE (60% vs. 56%; p = 0.7), grade ≥ 3 AE (0% vs. 11%; p = 0.3), objective response (58% total, 60% vs. 56%; p = 0.7), and complete response (16% total; 10% vs. 22%; p = 0.8) were similar between the atezolizumab/bevacizumab and the nivolumab cohorts. Median OS was 12.9 months for the whole cohort, 16.4 months for nivolumab, and 10.7 months for atezolizumab/bevacizumab. Among patients with advanced unresectable HCC, the utilization of Y90-RE concurrently or within 90 days of nivolumab or atezolizumab/bevacizumab immunotherapy, appears to be well-tolerated and with a low incidence of severe AE.
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Affiliation(s)
- Alexander Villalobos
- Department of Radiology, University of North Carolina at Chapel Hill, Alexander Villalobos 101 Manning Drive, Chapel Hill, NC 27514, USA;
| | - Howard Hussein Dabbous
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; (H.H.D.); (M.A.L.); (Z.B.)
| | - Olivia Little
- Department of Radiology and Imaging Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA;
| | - Olumide Babajide Gbolahan
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA;
| | - Mehmet Akce
- Department of Hematology and Medical Oncology, University of Alabama School of Medicine, Birmingham, AL 35294, USA;
| | - Meghan Allegra Lilly
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; (H.H.D.); (M.A.L.); (Z.B.)
| | - Zachary Bercu
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; (H.H.D.); (M.A.L.); (Z.B.)
| | - Nima Kokabi
- Department of Radiology, University of North Carolina at Chapel Hill, Alexander Villalobos 101 Manning Drive, Chapel Hill, NC 27514, USA;
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11
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Karim MA, Ramezani M, Leroux T, Kum HC, Singal AG. Healthcare Costs for Medicare Patients With Hepatocellular Carcinoma in the United States. Clin Gastroenterol Hepatol 2023; 21:2327-2337.e9. [PMID: 36435358 PMCID: PMC10205916 DOI: 10.1016/j.cgh.2022.11.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/12/2022] [Accepted: 11/04/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) has an increasing mortality in the United States and is a leading cause of morbidity and mortality in patients with cirrhosis. We aimed to estimate the financial burden related to HCC in a large nationally representative United States cohort. METHODS We used the Surveillance, Epidemiology, and End Results program (SEER)-Medicare database to identify 4525 adult patients who were diagnosed with HCC between 2011 and 2015. We generated a 1:1 propensity score-matched cohort of patients with cirrhosis but no HCC as a comparator group to define incremental HCC-specific costs beyond costs related to underlying cirrhosis. Our main outcomes were patient liabilities and Medicare payments in the first year after HCC diagnosis. RESULTS Compared with patients with cirrhosis, those with HCC had higher incremental patient liabilities (median +$7166; interquartile range, $2401-$16,099) and Medicare payments (+$50,110; interquartile range, $142,42-$136,239; P < .001 for both) in the first year after diagnosis. Patients with HCC had significantly higher inpatient, outpatient, and physician service costs compared with the matched cohort with cirrhosis (P < .001 for all). Patients with early-stage HCC had lower incremental patient liabilities (median, $4195 vs $8238; P < .001) and Medicare payments (median, $28,207 vs $59,509; P < .001) than those with larger tumor burden. In multivariable median regression analysis, incremental patient liabilities and Medicare payments were significantly associated with the National Cancer Institute comorbidity index, nonalcoholic fatty liver disease etiology, presence of ascites, and presence of hepatic encephalopathy. CONCLUSIONS Patients with HCC suffer from cancer-related financial burden, highlighting a need for policy interventions and financial support systems.
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Affiliation(s)
- Mohammad A Karim
- Population Informatics Laboratory, Department of Health Policy & Management, School of Public Health, Texas A&M University, College Station, Texas
| | - Mahin Ramezani
- Population Informatics Laboratory, Department of Health Policy & Management, School of Public Health, Texas A&M University, College Station, Texas
| | | | - Hye-Chung Kum
- Population Informatics Laboratory, Department of Health Policy & Management, School of Public Health, Texas A&M University, College Station, Texas
| | - Amit G Singal
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.
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12
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Asghar K, Bashir S, Ali Rana I, Abu Bakar M, Farooq A, Hassan M, Asif Z, Afzal M, Masood I, Ishaq M, Tahseen M, Bilal S, Mehmood S, Kanwal N, Ud Din I, Loya A. PD-L1 is Fascinating but IDO Needs Attention in Non-HCV and Non-HBV-Associated Hepatocellular Carcinoma Patients. J Hepatocell Carcinoma 2023; 10:921-934. [PMID: 37350801 PMCID: PMC10284167 DOI: 10.2147/jhc.s409741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 05/20/2023] [Indexed: 06/24/2023] Open
Abstract
Background/Aim Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer that is modulated by the immune system. Programmed cell death ligand-1 (PD-L1) has emerged as a novel therapeutic target in various cancers. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that is associated with poor prognoses in various cancer types. The aim of this study was to investigate the PD-L1 expression, and clinicopathological features of non-HCV and non-HBV-associated HCC patients, including IDO expression. Patients and Methods In this study, immunohistochemical analysis was performed to analyze the expression of PD-L1 and IDO. Formalin-fixed paraffin-embedded HCC tumor tissues (n=50) were obtained from the pathology department, at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC) in Lahore, Pakistan between 2005 and 2022. All the patients were HBV and HCV negative. Furthermore, it was a rare group of patients with no previous history of any viral hepatitis. In addition, for categorical and continuous variables chi-square or Fisher exact test and Mann-Whitney U-test was performed. Results Of 50 tissue specimens, PD-L1+ was observed in 21 [high: 12 (24%), low: 9 (18%)] and PD-L1- was observed in 29 HCC patients. IDO+ was observed in all 50 specimens [high: 42 (84%), low: 8 (16%)]. Additionally, both PD-L1 and IDO had high expression in 11 (22%) patients. While both PD-L1 and IDO had low expression in 2 (4%) patients. Furthermore, in IDO+/PD-L1- group, 20 (69%) out of 29 patients died while in the IDO+/PD-L1+ group, 9 (43%) out of 21 patients died. Conclusion Evaluation of IDO and PD-L1 expression may add therapeutic advantage in non-HCV and non-HBV-associated HCC patients that overexpress IDO. Further validation in a larger cohort is warranted.
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Affiliation(s)
- Kashif Asghar
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Shaarif Bashir
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Iftikhar Ali Rana
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Muhammad Abu Bakar
- Department of Cancer Registry and Clinical Data Management, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Asim Farooq
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Muhammad Hassan
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Zukhruf Asif
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Mahnoor Afzal
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Iqra Masood
- Department of Clinical Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Muhammad Ishaq
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Muhammad Tahseen
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Sundus Bilal
- Department of Internal Medicine (Gastroenterology), Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Shafqat Mehmood
- Department of Internal Medicine (Gastroenterology), Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Nosheen Kanwal
- Department of Radiology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Islah Ud Din
- Department of Radiology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
| | - Asif Loya
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Punjab, Pakistan
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13
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Criss CR, Makary MS. Salvage locoregional therapies for recurrent hepatocellular carcinoma. World J Gastroenterol 2023; 29:413-424. [PMID: 36688022 PMCID: PMC9850930 DOI: 10.3748/wjg.v29.i3.413] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 11/20/2022] [Accepted: 01/02/2023] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies, recurrence rates remain high. In contrast to first-line treatment for HCC, which relies on several factors, including clinical staging, tumor burden, and liver function, there is no consensus or general treatment recommendations for recurrent HCC (R-HCC). Locoregional therapies include a spectrum of minimally invasive liver-directed treatments which can be used as either curative or neoadjuvant therapy for HCC. Herein, we provide a comprehensive review of recent evidence using salvage loco-regional therapies for R-HCC after failed curative-intent.
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Affiliation(s)
- Cody R Criss
- Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, United States
| | - Mina S Makary
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, United States
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14
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Ouranos K, Chatziioannou A, Goulis I, Sinakos E. Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation. World J Transplant 2022; 12:331-346. [PMID: 36437845 PMCID: PMC9693898 DOI: 10.5500/wjt.v12.i11.331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/10/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver neoplasm that, according to tumor stage, can be treated with resection, transplantation, locoregional treatment options, or systemic therapy. Although interventions only in early-stage disease can offer complete tumor regression, systemic therapy in advanced disease can significantly prolong overall survival, according to published clinical trials. The emergence of immunotherapy in the field of cancer therapy has had a positive impact on patients with HCC, resulting in atezolizumab–bevacizumab currently being the first-line option for treatment of advanced HCC. In light of this, application of immunotherapy in the preoperative process could increase the number of patients fulfilling the criteria for liver transplantation (LT). Implementation of this approach is faced with challenges regarding the safety of immunotherapy and the possibly increased risk of rejection in the perioperative period. Case reports and clinical trials assessing the safety profile and effectiveness of neoadjuvant immunotherapy, highlight important aspects regarding this newly evolving approach to HCC management. More studies need to be conducted in order to reach a consensus regarding the optimal way to administer immunotherapy prior to LT. In this review, we summarize the role, safety profile and future considerations regarding the use of neoadjuvant immunotherapy prior to LT in patients with HCC.
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Affiliation(s)
- Konstantinos Ouranos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Anthi Chatziioannou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis Goulis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Emmanouil Sinakos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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15
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Is There a Place for Somatostatin Analogues for the Systemic Treatment of Hepatocellular Carcinoma in the Immunotherapy Era? LIVERS 2022. [DOI: 10.3390/livers2040024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Patients with advanced hepatocellular carcinoma (HCC) have a very limited survival rate even after the recent inclusion of kinase inhibitors or immune checkpoint inhibitors in the therapeutic armamentarium. A significant problem with the current proposed therapies is the considerable cost of treatment that may be a serious obstacle in low- and middle-income countries. Implementation of somatostatin analogues (SSAs) has the potential to overcome this obstacle, but due to some negative studies their extensive evaluation came to a halt. However, experimental evidence, both in vitro and in vivo, has revealed various mechanisms of the anti-tumor effects of these analogues, including inhibition of cancer cell proliferation and angiogenesis and induction of apoptosis. Favorable indirect effects such as inhibition of liver inflammation and fibrosis and influence on macrophage-mediated innate immunity have also been noted and are presented in this review. Furthermore, the clinical application of SSAs is both presented and compared with clinical trials of kinase and immune checkpoint inhibitors (ICIs). No direct trials have been performed to compare survival in the same cohort of patients, but the cost of treatment with SSAs is a fraction compared to the other modalities and with significantly less serious side effects. As in immunotherapy, patients with viral HCC (excluding alcoholics), as well as Barcelona stage B or C and Child A patients, are the best candidates, since they usually have a survival prospect of at least 6 months, necessary for optimum results. Reasons for treatment failures are also discussed and further research is proposed.
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16
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Xie Q, Zhang P, Wang Y, Mei W, Zeng C. Overcoming resistance to immune checkpoint inhibitors in hepatocellular carcinoma: Challenges and opportunities. Front Oncol 2022; 12:958720. [PMID: 36119533 PMCID: PMC9478417 DOI: 10.3389/fonc.2022.958720] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatocellular carcinoma is one of the leading causes of cancer mortality globally, and its incidence is increasing. Immune checkpoint therapy has revolutionized the treatment of hepatocellular carcinoma over the past few years. However, only a limited proportion of patients with hepatocellular carcinoma respond to immunotherapy. Despite the significant breakthroughs, the molecular mechanisms that drive immune responses and evasion are largely unresolved. Predicting tumor response and resistance to immune checkpoint inhibitors is a significant challenge. In this review, we focus on the current research progress of immune checkpoint inhibitors in hepatocellular carcinoma. Importantly, this review highlights the underlying mechanisms of resistance to immune checkpoint inhibitors and summarizes potential strategies to overcome the resistance to immune checkpoint inhibitors in hepatocellular carcinoma.
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Affiliation(s)
- Qingqing Xie
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, China
| | - Pengfei Zhang
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, China
| | - Yuanyuan Wang
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Wuxuan Mei
- Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Changchun Zeng
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, China
- *Correspondence: Changchun Zeng,
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17
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Ayoub WS, Jones PD, Yang JD, Martin P. Emerging drugs for the treatment of hepatocellular carcinoma. Expert Opin Emerg Drugs 2022; 27:141-149. [PMID: 35642526 DOI: 10.1080/14728214.2022.2083107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) remains a leading cause of liver related mortality. Cirrhosis of any etiology is the major risk factor although HCC can develop in its absence in patients with Hepatitis B and increasingly in those with non-alcoholic fatty liver disease. When detected at an early stage, curative options include surgical resection, liver transplantation and/or ablative therapies. Unfortunately, most cases of HCC are recognized at an advanced state when options are limited and non-curative. However new systemic therapies with tyrosine kinase inhibitors and immunotherapy have expanded therapeutic options in advanced HCC. Advances in systemic therapy have given patients with advanced HCC hope and prolonged their survival. Ongoing trials addressing different combination therapies with checkpoint inhibitors, tyrosine kinase inhibitors (TKI) or anti-VEGF therapies are expected to further enhance the management of advanced HCC. AREAS COVERED We discuss recent data and ongoing research efforsts to improve the treatment of hepatocellular carcinoma with discussion of current and upcoming systemic therapy combining agents of different classes. EXPERT OPINION Sustemic therapy for HCC is in evolution. The inclusion of immunotherapy to systemic therapy has revolutionalized the field of HCC treatment. Identificantion of the appropriate combination and sequence of systemic therapy coupled with discovery of reliable HCC biomarkers will lead to improved survival and inidividulized HCC therapy.
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Affiliation(s)
- Walid S Ayoub
- Cedars-Sinai Medical Center, Los Angeles, United States
| | - Patricia D Jones
- University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Ju Dong Yang
- Cedars-Sinai Medical Center, Los Angeles, United States
| | - Paul Martin
- University of Miami Miller School of Medicine, Miami, Florida, United States
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18
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Xu L, Ling J, Su C, Su YW, Xu Y, Jiang Z. Emerging Roles on Immunological Effect of Indoleamine 2,3-Dioxygenase in Liver Injuries. Front Med (Lausanne) 2021; 8:756435. [PMID: 34869457 PMCID: PMC8636938 DOI: 10.3389/fmed.2021.756435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well as current challenges for IDO targets. In particular, we discuss unexpected conclusions against previous work published. IDO is induced by pro-inflammatory cytokines in liver dysfunction and exerts an immunosuppressive effect, whereas the improvement of liver injury may require consideration of multiple factors besides IDO.
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Affiliation(s)
- Lingyan Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Jiawei Ling
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China
| | - Chang Su
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yu-Wen Su
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Yan Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Zhenzhou Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
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19
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Wang Y, Zhou C, Liu J, Shi Q, Huang S, Yang C, Li T, Chen Y, Xiong B. Increased Liquefactive Necrosis Formation After Transarterial Chemoembolization Combined with Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Hepatocellular Carcinoma. Cancer Manag Res 2021; 13:6935-6941. [PMID: 34522136 PMCID: PMC8434848 DOI: 10.2147/cmar.s328812] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 08/28/2021] [Indexed: 12/24/2022] Open
Abstract
PURPOSE In clinical practice, we found some of the patients who received transarterial chemoembolization (TACE) with molecular targeted agents (MTGs) plus immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) had obvious liquefactive necrosis formation within the tumor and some even progressed to a liver abscess, which seems more frequent than patients who received other treatments. Thus, we aim to identify this condition and analyze the potential risk factors. PATIENTS AND METHODS Medical records of 72 consecutive patients with intermediate (BCLC B) and advanced (BCLC C) HCC who received TACE plus MTGs combined with (n=30) or without (n=42) ICIs were reviewed. Liquefactive necrosis formation was defined as the presence of obvious liquefactive necrosis within the tumor that required intervention. RESULTS The liquefactive necrosis rate was higher in the TACE+MTGs+ICIs group than in the TACE+MTGs group (30% vs 4.8%, P=0.006). Moreover, 18.2% (2/11) of the patients with liquefactive necrosis within the tumor had a bacterial infection. We then take the binary logistic regression analysis model to identify the predictors of liquefactive necrosis formation, and which showed the tumor size (P=0.006, OR=1.355, 95% CI: 1.090-1.684), alpha-fetoprotein level (P=0.036, OR=6.745, 95% CI: 1.130-40.262) and treatment modality (P=0.015, OR=11.717, 95% CI: 1.617-84.887) were the independent risk factor for liquefactive necrosis formation within the tumor. CONCLUSION Patients with HCC who received TACE combined with MTGs plus ICIs have increased liquefactive necrosis formation, and the larger tumor size and higher alpha-fetoprotein level were associated with more liquefactive necrosis formation within the tumor.
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Affiliation(s)
- Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Qin Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Songjiang Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Chongtu Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Tongqiang Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Yang Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
| | - Bin Xiong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of China
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20
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The State of Immunotherapy in Hepatobiliary Cancers. Cells 2021; 10:cells10082096. [PMID: 34440865 PMCID: PMC8393650 DOI: 10.3390/cells10082096] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/02/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC), are lethal cancers with limited therapeutic options. Curative-intent treatment typically involves surgery, yet recurrence is common and many patients present with advanced disease not amenable to an operation. Immunotherapy represents a promising approach to improve outcomes, but the immunosuppressive tumor microenvironment of the liver characteristic of hepatobiliary cancers has hampered the development and implementation of this therapeutic approach. Current immunotherapies under investigation include immune checkpoint inhibitors (ICI), the adoptive transfer of immune cells, bispecific antibodies, vaccines, and oncolytic viruses. Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two ICIs that have demonstrated utility in HCC, and newer immune checkpoint targets are being tested in clinical trials. In advanced CCA and GBC, PD-1 ICIs have resulted in antitumor responses, but only in a minority of select patients. Other ICIs are being investigated for patients with CCA and GBC. Adoptive transfer may hold promise, with reports of complete durable regression in metastatic CCA, yet this therapeutic approach may not be generalizable. Alternative approaches have been developed and promising results have been observed, but clinical trials are needed to validate their utility. While the treatment of hepatobiliary cancers involves unique challenges that these cancers present, the progress seen with ICIs and adoptive transfer has solidified immunotherapy as an important approach in these challenging patients with few other effective treatment options.
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