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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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de Andrade AG, Vanderley SER, de Farias Marques L, Almeida FS, Cavalcante-Silva LHA, Keesen TSL. Leptin, NK cells, and the weight of immunity: Insights into obesity. Int Immunopharmacol 2025; 147:113992. [PMID: 39755107 DOI: 10.1016/j.intimp.2024.113992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/28/2024] [Accepted: 12/29/2024] [Indexed: 01/06/2025]
Abstract
Obesity is a chronic inflammatory disease that affects more than 1 billion people worldwide and is associated with various metabolic and physiological dysfunctions, directly impacting the dynamics of the immune response, partly due to elevated leptin levels. Leptin is an important peptide hormone that regulates neuroendocrine function and energy homeostasis, with its blood levels reflecting energy reserves, fat mass, or energy deprivation. This hormone also plays a fundamental role in regulating immune function, including the activity of NK cells, which are essential components in antiviral and antitumor activity. In obese individuals, leptin resistance is commonly established, however, NK cells and other immune components remain responsive to this hormone. So far, leptin has demonstrated paradoxical activities of these cells, often associated with a dysfunctional profile when associated with obesity. The excessive fat is usually related to metabolic remodeling in NK cells, resulting in compromised antitumor responses due to reduced cytotoxic capacity and decreased expression of cytokines important for these defense mechanisms, such as IFN-γ. Therefore, this review approaches a better understanding of the immunoendocrine interactions between leptin and NK cells in the context of obesity.
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Affiliation(s)
- Arthur Gomes de Andrade
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | - Shayenne Eduarda Ramos Vanderley
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | - Lorrane de Farias Marques
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | - Fernanda Silva Almeida
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil
| | | | - Tatjana Souza Lima Keesen
- Immunology Laboratory of Infectious Diseases, Department of Cellular and Molecular Biology, Federal University of Paraiba, João Pessoa, Paraíba 58051-900, Brazil.
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Pogoda-Wesołowska A, Sługocka N, Synowiec A, Brodaczewska K, Mejer-Zahorowski M, Ziękiewicz M, Szypowski W, Szymański P, Stępień A. The current state of knowledge on the role of NKG2D ligands in multiple sclerosis and other autoimmune diseases. Front Mol Neurosci 2025; 17:1493308. [PMID: 39866909 PMCID: PMC11758245 DOI: 10.3389/fnmol.2024.1493308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/18/2024] [Indexed: 01/28/2025] Open
Abstract
Multiple sclerosis (MS) is a chronic central nervous system (CNS) disease with demyelinating inflammatory characteristics. It is the most common nontraumatic and disabling disease affecting young adults. The incidence and prevalence of MS have been increasing. However, its exact cause remains unclear. The main tests used to support the diagnosis are magnetic resonance imaging (MRI) examination and cerebrospinal fluid (CSF) analysis. Nonetheless, to date, no sensitive or specific marker has been identified for the detection of the disease at its initial stage. In recent years, researchers have focused on the fact that the number of natural killer cell group 2 member D (NKG2D) family of C-type lectin-like receptor + (NKG2D+) T cells in the peripheral blood, CSF, and brain tissue has been shown to be higher in patients with MS than in controls. The activating receptor belonging to the NKG2D is stimulated by specific ligands: in humans these are major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) and MHC class I polypeptide-related sequence B (MICB) proteins and UL16 binding 1-6 proteins (ULBP1-6). Under physiological conditions, the aforementioned ligands are expressed at low or undetectable levels but can be induced in response to stress factors. NKG2D ligands (NKG2DLs) are involved in epigenetic regulation of their expression. To date, studies in cell cultures, animal models, and brain tissues have revealed elevated expression of MICA/B, ULPB4, and its mouse homolog murine UL16 binding protein-like transcript (MULT1), in oligodendrocytes and astrocytes from patients with MS. Furthermore, soluble forms of NKG2DLs were elevated in the plasma and CSF of patients with MS compared to controls. In this review, we aim to describe the role of NKG2D and NKG2DLs, and their interactions in the pathogenesis of MS, as well as in other autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and celiac disease (CeD). We also assess the potential of these proteins as diagnostic markers and consider future perspectives for targeting NKG2D ligands and their pathways as therapeutic targets in MS.
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Affiliation(s)
| | - Nina Sługocka
- Faculty of Medicine, University of Warsaw, Warsaw, Poland
| | - Agnieszka Synowiec
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine–National Research Institute, Warsaw, Poland
| | - Klaudia Brodaczewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine–National Research Institute, Warsaw, Poland
| | - Marcin Mejer-Zahorowski
- Neurology Clinic, Military Institute of Medicine- National Research Institute, Warsaw, Poland
| | - Maciej Ziękiewicz
- Neurology Clinic, Military Institute of Medicine- National Research Institute, Warsaw, Poland
| | - Wojciech Szypowski
- Neurology Clinic, Military Institute of Medicine- National Research Institute, Warsaw, Poland
| | - Piotr Szymański
- Neurology Clinic, Military Institute of Medicine- National Research Institute, Warsaw, Poland
| | - Adam Stępień
- Neurology Clinic, Military Institute of Medicine- National Research Institute, Warsaw, Poland
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Zhang X, Dai S, Li L, Wang P, Dong M. UL16‑binding protein 1 is a significant prognostic and diagnostic marker for breast cancer. Oncol Lett 2025; 29:15. [PMID: 39492940 PMCID: PMC11526324 DOI: 10.3892/ol.2024.14761] [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: 05/17/2024] [Accepted: 09/05/2024] [Indexed: 11/05/2024] Open
Abstract
The aim of the present study was to investigate the association between UL16 binding protein 1 (ULBP1) and the prognosis of patients with and immune cell infiltration in breast cancer (BRCA). The mRNA data of BRCA and immune-related genes were extracted from The Cancer Genome Atlas and were analyzed using bioinformatics tools. Subsequently, the results obtained by bioinformatics were validated through the collection of clinical patient data at the Zibo Central hospital (Zibo, China). The difference in the expression of the ULBP1 gene between BRCA tissues and normal precancerous tissues was analyzed, followed by validation using immunohistochemistry. By combining clinical data from patients with BRCA, the prognostic and diagnostic significance of the ULBP1 gene in patients with BRCA was analyzed. Gene enrichment analysis was conducted to gain insight into the molecular mechanisms underlying the regulatory role of ULBP1 in BRCA by analyzing its related functions and signaling pathways. Furthermore, single sample gene set enrichment analysis (ssGSEA) and Spearman's correlation analysis were performed to explore the correlation between ULBP1 as a target gene related with tumor immune cell infiltration. The data revealed that ULBP1 is a target gene associated with immunity and the prognosis of patients with BRCA. Patients with BRCA with a high expression of ULBP1 had a poorer prognosis. ULBP1 expression correlated with progesterone receptor expression, estrogen receptor expression and histological type in patients with BRCA; thus, it may serve as an independent predictor for the overall survival rate of patients. Functional enrichment analysis revealed a significant co-expression between ULBP1 and ULBP2, ULBP3, retinoic acid early transcript 1K, as well as a significant enrichment of pathways associated with carcinogenesis and immune suppression. ssGSEA and Spearman's correlation analysis demonstrated significant correlations between ULBP1 expression and tumor immune cells, as well as immune checkpoints. Overall, the present study demonstrated that ULBP1 was associated with BRCA immunity and might serve as a prognostic and diagnostic biomarker for patients with BRCA. In addition, it might also be a potential target for the immunotherapy of BRCA.
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Affiliation(s)
- Xiaowei Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong 266023, P.R. China
- Department of Orthopedics, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
| | - Shuhong Dai
- Department of Cardiology, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
| | - Liang Li
- Department of Orthopedics, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
| | - Pengyun Wang
- Department of Orthopedics, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
| | - Mingxin Dong
- Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong 266023, P.R. China
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Arrè V, Negro R, Giannelli G. The role of inflammasomes in hepatocellular carcinoma: Mechanisms and therapeutic insights. Ann Hepatol 2024; 30:101772. [PMID: 39701280 DOI: 10.1016/j.aohep.2024.101772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024]
Abstract
Hepatocellular carcinoma is among the most frequent forms of primary liver cancer and develops within a context of chronic inflammation, frequently associated with a multitude of risk factors, including viral infections, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis and liver fibrosis. The tumor microenvironment is crucial for the progression of HCC, as immune cells, tumor-associated fibroblasts and hepatic stellate cells interact to promote chronic inflammation and tumor spread. Inflammasomes, the multiprotein complexes that launch the innate immune response, emerge as important mediators in the pathogenesis of HCC. Among others, the inflammasome Nucleotide-binding oligomerization domain, Leucine rich Repeat (NLR) and Pyrin (NLRP) 3 (NLRP3), and absent in melanoma 2 (AIM2), exhibit a dual role in HCC background. It has been reported that they can exert oncosuppressive functions by triggering the inflammatory death of cancer cells. Vice versa, chronic activation contributes to the development of a pro-tumorigenic environment, thus supporting tumor growth. In addition, other inflammasomes such as Nucleotide-binding oligomerization domain, Leucine rich Repeat (NLR) and Pyrin (NLRP) 6 and 12 (NLRP6 and NLRP12, respectively) regulate HCC onset and progression, although more experimental evidence is required. This review focuses on the molecular mechanisms underpinning the inflammasome's contribution to the onset, progression and spread of HCC. Moreover, we will explore the potential therapeutic approaches currently under investigation, which aim to improve the efficacy and reduce the side effects of the treatments currently available. Targeting inflammasomes may be a promising therapeutic strategy for the treatment of HCC, offering new opportunities to improve patient prognosis.
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Affiliation(s)
- Valentina Arrè
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy.
| | - Roberto Negro
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy.
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, "S. de Bellis", IRCCS Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy.
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Kim MS, Jeon S, Lee HJ, Ri HS, Cho AR, Park EJ, Yeo JS, Kim JH, Lee J. NKG2D (Natural Killer Group 2, Member D) ligand expression and ameloblastoma recurrence: a retrospective immunohistological pilot study. BMC Oral Health 2024; 24:1102. [PMID: 39289711 PMCID: PMC11409757 DOI: 10.1186/s12903-024-04873-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND/PURPOSE This retrospective immunohistological pilot study aimed to investigate the influence of natural killer group 2, member D (NKG2D) ligand expression on ameloblastoma recurrence after surgical resection. It also aimed to elucidate additional clinical factors that could serve as predictors of ameloblastoma recurrence. MATERIALS AND METHODS This study included 96 patients who were histologically diagnosed with ameloblastoma after surgical resection. The expression of NKG2D ligands, including UL16-binding proteins (ULBPs) 1-3 and major histocompatibility complex class I chain-related molecule (MIC) A/B, was evaluated in formalin-fixed paraffin-embedded tumor tissues via immunohistochemistry assays. Furthermore, the patients' electronic medical records were reviewed. Multivariate Cox regression analysis was conducted, and data were expressed as adjusted hazard ratios [HRs] with 95% confidence intervals [95% CIs]. RESULTS Multivariate analysis revealed that recurrent tumors (ref.: primary; adjusted HR [95% CI]: 2.780 [1.136, 6.803], p = 0.025) and positive MICA/B expression (ref.: negative; adjusted HR [95% CI]: 0.223 [0.050, 0.989], p = 0.048) independently affected recurrence-free survival in ameloblastoma. CONCLUSION This study identified recurrent cases and loss of MICA/B expression as independent predictors of early ameloblastoma recurrence following surgical resection. The findings suggest that decreased MICA/B expression might undermine NKG2D-mediated tumor immunosurveillance, thereby influencing early recurrence.
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Affiliation(s)
- Mee-Seon Kim
- Department of Pathology, School of Dentistry, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Soeun Jeon
- Department of Anesthesia and Pain Medicine, School of Dentistry, Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, Republic of Korea.
- Department of Anesthesia and Pain Medicine, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, Republic of Korea.
| | - Hyeon Jeong Lee
- Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Busan, Republic of Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Hyun-Su Ri
- Department of Anesthesia and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ah-Reum Cho
- Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Busan, Republic of Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Eun Ji Park
- Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Busan, Republic of Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Jin Song Yeo
- Department of Anesthesia and Pain Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Han Kim
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Jiyoun Lee
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
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Shin SK, Oh S, Chun SK, Ahn MJ, Lee SM, Kim K, Kang H, Lee J, Shin SP, Lee J, Jung YK. Immune signature and therapeutic approach of natural killer cell in chronic liver disease and hepatocellular carcinoma. J Gastroenterol Hepatol 2024; 39:1717-1727. [PMID: 38800890 DOI: 10.1111/jgh.16584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 03/14/2024] [Accepted: 04/11/2024] [Indexed: 05/29/2024]
Abstract
Natural killer (NK) cells are one of the key members of innate immunity that predominantly reside in the liver, potentiating immune responses against viral infections or malignant tumors. It has been reported that changes in cell numbers and function of NK cells are associated with the development and progression of chronic liver diseases (CLDs) including non-alcoholic fatty liver disease, alcoholic liver disease, and chronic viral hepatitis. Also, it is known that the crosstalk between NK cells and hepatic stellate cells plays an important role in liver fibrosis and cirrhosis. In particular, the impaired functions of NK cells observed in CLDs consequently contribute to occurrence and progression of hepatocellular carcinoma (HCC). Chronic infections by hepatitis B or C viruses counteract the anti-tumor immunity of the host by producing the sheddases. Soluble major histocompatibility complex class I polypeptide-related sequence A (sMICA), released from the cell surfaces by sheddases, disrupts the interaction and affects the function of NK cells. Recently, the MICA/B-NK stimulatory receptor NK group 2 member D (NKG2D) axis has been extensively studied in HCC. HCC patients with low membrane-bound MICA or high sMICA concentration have been associated with poor prognosis. Therefore, reversing the sMICA-mediated downregulation of NKG2D has been proposed as an attractive strategy to enhance both innate and adaptive immune responses against HCC. This review aims to summarize recent studies on NK cell immune signatures and its roles in CLD and hepatocellular carcinogenesis and discusses the therapeutic approaches of MICA/B-NKG2D-based or NK cell-based immunotherapy for HCC.
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Affiliation(s)
- Seung Kak Shin
- Division of Gastroenterology and Hepatology, Department of Internal medicine, Gachon University Gil Medical Center, College of Medicine, Gachon University, Incheon, South Korea
| | - Sooyeon Oh
- Chaum Life Center, School of Medicine, CHA University, Seoul, South Korea
| | - Su-Kyung Chun
- Chaum Life Center, School of Medicine, CHA University, Seoul, South Korea
| | - Min-Ji Ahn
- Center for Research and Development, CHA Advanced Research Institute, Seoul, South Korea
| | - Seung-Min Lee
- Center for Research and Development, CHA Advanced Research Institute, Seoul, South Korea
| | - Kayun Kim
- School of Medicine, CHA University, Seoul, South Korea
| | - Hogyeong Kang
- School of Medicine, CHA University, Seoul, South Korea
| | - Jeongwoo Lee
- School of Medicine, CHA University, Seoul, South Korea
| | - Suk Pyo Shin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Jooho Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, South Korea
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Phanabamrung S, Jumnainsong A, Anuwongcharoen N, Phanus-Umporn C, Rareongjai S, Leelayuwat C. Expression and function of the major histocompatibility complex (MHC) class I chain-related A (MICA)*010 in NK cell killing activity. Hum Immunol 2024; 85:111085. [PMID: 39116667 DOI: 10.1016/j.humimm.2024.111085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 07/19/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024]
Abstract
The major histocompatibility complex (MHC) class I chain-related A (MICA) plays an important role in stress cell recognition. High polymorphisms of MICA are relevant to NKG2D binding capacity, responses of NK cells and tumor progression. In this study, MICA genotyping of 97 cholangiocarcinoma patients was performed using PCR-SSP. MICA*010 was positively associated with a corrected p-value of < 0.001 (RR=2.16 (95 % CI, 1.48-3.14)). MICA*010 was previously reported as a non-expressed allele. Thus, the expression of MICA*010 on the cell surface was studied on both MICA*010 transfected cells (HEK 293 T and L929 cells) and stimulated primary monocytes obtained from homozygous MICA*010 individuals using different clones of antibodies (1H10, 1D10, 1C3.1, 1C3.2, 6D4 and 3H5) for detection. Surprisingly, the expression of MICA*010 could be observed on both transfected cells and stimulated monocytes and effectively bound to the NKG2D-Fc fusion protein. The functional study of various MICA alleles revealed the high relative killing activity of NK cells induced by the MICA*010 transfected C1R cells, not following the previously reported rule of the M129V substitution. The structural analysis highlighted the amino acid at position 36 as another important amino acid relevant to preserving the structural integrity of the MICA protein and NKG2D binding. Our data propose a new aspect of functional MICA contributing motifs and that MICA*010 has a potential effect on NK cell functions and might be applicable to other fields of immune responses.
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Affiliation(s)
- Sonwit Phanabamrung
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand; The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Amonrat Jumnainsong
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Nuttapat Anuwongcharoen
- Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Chuleeporn Phanus-Umporn
- Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Sarayot Rareongjai
- Unit of Excellence in Immunodiagnostic, School of Allied Health Sciences, University of Phayao, Mueang, Phayao 56000, Thailand
| | - Chanvit Leelayuwat
- The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
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Rademacher MJ, Faber ML, Bone KM, Medin JA, Schloemer NJ. Fate control engagement augments NK cell responses in LV/hu-IL-12 transduced sarcoma. Exp Mol Pathol 2024; 137:104898. [PMID: 38729059 DOI: 10.1016/j.yexmp.2024.104898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 04/23/2024] [Accepted: 05/01/2024] [Indexed: 05/12/2024]
Abstract
INTRODUCTION NK cells are an untapped resource for cancer therapy. Sarcomas transduced with lentiviruses to express human IL-12 are only cleared in mice bearing mature human NK cells. However, systemic inflammation limits IL-12 utilization. Fate control a.k.a. "suicide mechanisms" regulate unchecked systemic inflammation caused by cellular immunotherapies. Despite increasing utilization, there remains limited data on immune consequences or tumor-directed effects of fate control. OBJECTIVES We sought to engage the mutant thymidylate kinase (mTMPK) metabolic fate control system to regulate systemic inflammation and assess the impact on NK cell effector functions. METHODS Primary human sarcoma short-passage samples and cell lines were transduced with LV/hu-IL-12_mTMPK engineering expression of IL-12 and an AZT-associated fate control enzyme. We assessed transduced sarcoma responses to AZT engagement and subsequent modulation of NK cell functions as measured by inflammatory cytokine production and cytotoxicity. RESULTS AZT administration to transduced (LV/hu-IL-12_mTMPK) short-passage primary human sarcomas and human Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines, abrogated the robust expression of human IL-12. Fate control activation elicited a specific dose-dependent cytotoxic effect measured by metabolic activity (WST-1) and cell death (Incucyte). NK effector functions of IFN-γ and cytotoxic granule release were significantly augmented despite IL-12 abrogation. This correlated with preferentially induced expression of NK cell activation ligands. CONCLUSIONS mTMPK fate control engagement terminates transduced sarcoma IL-12 production and triggers cell death, but also augments an NK cell-mediated response coinciding with metabolic stress activating surface ligand induction. Fate control engagement could offer a novel immune activation method for NK cell-mediated cancer clearance.
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Affiliation(s)
- Mary Jo Rademacher
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Mary L Faber
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Kathleen M Bone
- Departments of Pathology; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Jeffrey A Medin
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA; Departments of Biochemisty; Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Nathan J Schloemer
- Departments of Pediatrics; Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Arai J, Okumura A, Kato N, Ito K. Natural killer group 2D-major histocompatibility complex class I polypeptide-related sequence A activation enhances natural killer cell-mediated immunity against hepatocellular carcinoma: A review. Hepatol Res 2024; 54:420-428. [PMID: 38536662 DOI: 10.1111/hepr.14038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/26/2024] [Accepted: 03/09/2024] [Indexed: 05/03/2024]
Abstract
The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%-50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta-analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome-wide association study on chronic viral hepatitis showed that a single-nucleotide polymorphism of major histocompatibility complex class I polypeptide-related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single-nucleotide polymorphism-driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane-bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell-mediated cytotoxicity.
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Affiliation(s)
- Jun Arai
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Akinori Okumura
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
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Yin KL, Chu KJ, Li M, Duan YX, Yu YX, Kang MQ, Fu D, Liao R. Immune Regulatory Networks and Therapy of γδ T Cells in Liver Cancer: Recent Trends and Advancements. J Clin Transl Hepatol 2024; 12:287-297. [PMID: 38426194 PMCID: PMC10899867 DOI: 10.14218/jcth.2023.00355] [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: 08/10/2023] [Revised: 11/20/2023] [Accepted: 12/19/2023] [Indexed: 03/02/2024] Open
Abstract
The roles of γδ T cells in liver cancer, especially in the potential function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines, have aroused research interest. This review briefly describes the basic characteristics of γδ T cells, focusing on their diverse effects on liver cancer. In particular, different subtypes of γδ T cells have diverse or even opposite effects on liver cancer. We provide a detailed description of the immune regulatory network of γδ T cells in liver cancer from two aspects: immune components and nonimmune components. The interactions between various components in this immune regulatory network are dynamic and pluralistic, ultimately determining the biological effects of γδ T cells in liver cancer. We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment, emphasizing the potential of these cells in liver cancer immunotherapy.
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Affiliation(s)
- Kun-Li Yin
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai-Jian Chu
- Biliary Surgical Department I, the Eastern Hepatobiliary Surgical Hospital, Naval Medical University, Shanghai, China
| | - Ming Li
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu-Xin Duan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan-Xi Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mei-Qing Kang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Da Fu
- General Surgery, Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rui Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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12
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Soliman N, Saharia A, Abdelrahim M, Connor AA. Molecular profiling in the management of hepatocellular carcinoma. Curr Opin Organ Transplant 2024; 29:10-22. [PMID: 38038621 DOI: 10.1097/mot.0000000000001124] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to both summarize the current knowledge of hepatocellular carcinoma molecular biology and to suggest a framework in which to prospectively translate this knowledge into patient care. This is timely as recent guidelines recommend increased use of these technologies to advance personalized liver cancer care. RECENT FINDINGS The main themes covered here address germline and somatic genetic alterations recently discovered in hepatocellular carcinoma, largely owing to next generation sequencing technologies, and nascent efforts to translate these into contemporary practice. SUMMARY Early efforts of translating molecular profiling to hepatocellular carcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking are a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care.
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13
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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14
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Nguyen T, Chen PC, Pham J, Kaur K, Raman SS, Jewett A, Chiang J. Current and Future States of Natural Killer Cell-Based Immunotherapy in Hepatocellular Carcinoma. Crit Rev Immunol 2024; 44:71-85. [PMID: 38618730 DOI: 10.1615/critrevimmunol.2024052486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Natural killer (NK) cells are innate lymphoid cells that exhibit high levels of cytotoxicity against NK-specific targets. NK cells also produce various cytokines, and interact with T cells, B cells, and dendritic cells to effectively serve as frontliners of the innate immune system. Produce various cytokines, and interact with T cells, B cells, and dendritic cells to effectively serve as frontliners of the innate immune system. Moreover, NK cells constitute the second most common immune cell in the liver. These properties have drawn significant attention towards leveraging NK cells in treating liver cancer, especially hepatocellular carcinoma (HCC), which accounts for 75% of all primary liver cancer and is the fourth leading cause of cancer-related death worldwide. Notable anti-cancer functions of NK cells against HCC include activating antibody-dependent cell cytotoxicity (ADCC), facilitating Gasdermin E-mediated pyroptosis of HCC cells, and initiating an antitumor response via the cGAS-STING signaling pathway. In this review, we describe how these mechanisms work in the context of HCC. We will then discuss the existing preclinical and clinical studies that leverage NK cell activity to create single and combined immunotherapies.
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Affiliation(s)
- Tu Nguyen
- UCLA David Geffen School of Medicine
| | - Po-Chun Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Janet Pham
- Department of Radiology, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
| | - Kawaljit Kaur
- Division of Oral Biology and Medicine The Jane and Jerry Weintraub Center of Reconstructive Biotechnology University of California School of Dentistry Los Angeles, CA, USA
| | - Steven S Raman
- Department of Radiology, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Jason Chiang
- Department of Radiology, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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15
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Elbahrawy A, Atalla H, Mahmoud AA, Eliwa A, Alsawak A, Alboraie M, Madian A, Alashker A, Mostafa S, Alwassief A, Aly HH. Prediction and surveillance of de novo HCC in patients with compensated advanced chronic liver disease after hepatitis C virus eradication with direct antiviral agents. FRONTIERS IN VIROLOGY 2023; 3. [DOI: 10.3389/fviro.2023.1227317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The risk of hepatocellular carcinoma (HCC) diminishes in patients with hepatitis C virus (HCV)-related advanced chronic liver disease after virological cure. However, despite viral clearance, HCV-induced epigenetic alterations, immune dysregulations, and hepatic parenchymal injuries remain, contributing to de novo HCC occurrence. While HCC incidence is low (0.45 – 0.5%) in patients with advanced fibrosis (F3), the presence of liver cirrhosis and clinically significant portal hypertension increases the HCC risk. The cost-effectiveness of lifelong HCC surveillance in patients with compensated advanced chronic liver disease (cACLD) has sparked debate, raising questions about the most reliable noninvasive tests and stratification models for predicting HCC in patients with sustained virological response (SVR). Furthermore, identifying cACLD patients who may not require long-term HCC surveillance after SVR remains crucial. Several HCC risk stratification scores have been suggested for patients with cACLD, and emerging evidence supports individualized care based on personalized risk assessments. This review focuses on revising the pretreatment and posttreatment predictors of HCC, as well as the indications for HCC surveillance in cACLD patients treated with direct-acting antivirals.
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16
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Tan G, Spillane KM, Maher J. The Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer. BIOLOGY 2023; 12:1079. [PMID: 37626965 PMCID: PMC10452210 DOI: 10.3390/biology12081079] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/22/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023]
Abstract
The family of human NKG2D ligands (NKG2DL) consists of eight stress-induced molecules. Over 80% of human cancers express these ligands on the surface of tumour cells and/or associated stromal elements. In mice, NKG2D deficiency increases susceptibility to some types of cancer, implicating this system in immune surveillance for malignancy. However, NKG2DL can also be shed, released via exosomes and trapped intracellularly, leading to immunosuppressive effects. Moreover, NKG2D can enhance chronic inflammatory processes which themselves can increase cancer risk and progression. Indeed, tumours commonly deploy a range of countermeasures that can neutralise or even corrupt this surveillance system, tipping the balance away from immune control towards tumour progression. Consequently, the prognostic impact of NKG2DL expression in human cancer is variable. In this review, we consider the underlying biology and regulation of the NKG2D/NKG2DL system and its expression and role in a range of cancer types. We also consider the opportunities for pharmacological modulation of NKG2DL expression while cautioning that such interventions need to be carefully calibrated according to the biology of the specific cancer type.
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Affiliation(s)
- Ge Tan
- CAR Mechanics Group, Guy’s Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, Great Maze Pond, London SE1 9RT, UK;
| | | | - John Maher
- CAR Mechanics Group, Guy’s Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, Great Maze Pond, London SE1 9RT, UK;
- Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne BN21 2UD, UK
- Leucid Bio Ltd., Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
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17
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Jiang H, Fu H, Min T, Hu P, Shi J. Magnetic-Manipulated NK Cell Proliferation and Activation Enhance Immunotherapy of Orthotopic Liver Cancer. J Am Chem Soc 2023. [PMID: 37262421 DOI: 10.1021/jacs.3c02049] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
The immunotherapy of deep solid tumors in the human body, such as liver cancer, still faces great challenges, especially the inactivation and insufficient infiltration of immune cells in solid tumor microenvironment. Natural killer (NK) cells are gaining ever-increasing attention owing to their unique features and are expected to play an important role in the liver cancer immunotherapy. However, NK cells are severely insufficient and inactivated in solid liver tumor due to the highly immunosuppressive intratumor microenvironment, resulting in poor clinical therapeutic efficacy. Herein, we propose a mild magnetocaloric regulation approach using a magnetogenetic nanoplatform MNPs@PEI-FA/pDNA (MPFD), which is synthesized by loading a heat-inducible plasmid DNA (HSP70-IL-2-EGFP) on polyethyleneimine (PEI)- and folic acid (FA)-modified ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles (MNPs) to promote the proliferation and activation of tumor-infiltrating NK cells under magnetic manipulation without the limitation of penetration depth for orthotopic liver cancer immunotherapy. The magnetothermally responsive MPFD serves as a magnetism-heat nanotransducer to induce the gene transcription of IL-2 cytokine in orthotopic liver tumor for NK cell proliferation and activation. Both in vitro and in vivo results demonstrate that the remote mild magnetocaloric regulation (∼40 °C) by MPFD initiates the HSP70 promoter to trigger the overexpression of IL-2 cytokine for subsequent secretion, leading to in situ expansion and activation of tumor-infiltrating NK cells through the IL-2/IL-2 receptor (IL-2R) pathways and the resulting prominent tumor inhibition. This work not only evidences the great potential of magnetogenetic nanoplatform but also reveals the underlying proliferation and activation mechanism of NK cells in liver cancer treatment by magnetogenetic nanoplatform.
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Affiliation(s)
- Han Jiang
- Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hao Fu
- Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences, Shanghai 200050, China
| | - Tao Min
- Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ping Hu
- Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences, Shanghai 200050, China
- Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jianlin Shi
- Shanghai Institute of Ceramics, Chinese Academy of Sciences; Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease, Chinese Academy of Medical Sciences, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
- Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
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18
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Chen D, Gao J, Ren L, Chen P, Yang Y, She S, Xie Y, Liao W, Chen H. A signature based on NKG2D ligands to predict the recurrence of hepatocellular carcinoma after radical resection. Cancer Med 2023; 12:6337-6347. [PMID: 36210637 PMCID: PMC10028019 DOI: 10.1002/cam4.5318] [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: 07/21/2022] [Revised: 09/08/2022] [Accepted: 09/20/2022] [Indexed: 11/08/2022] Open
Abstract
INTRODUCTION Due to the high recurrence, the HCC prognosis remains poor. Yet, the biomarkers for predicting the recurrence of high-risk patients are currently lacking. We aimed to develop a signature to predict the recurrence of HCC based on NKG2D ligands. METHODS The multivariate Cox proportional hazards regression was used to select recurrence-related variables of NKG2D ligands in HCC patients from The Cancer Genome Atlas (TCGA). HCC patients from the OEP000321 dataset and Guilin cohort were used to validate the predictive signature. The mRNA expression of NKG2D ligands was measured by QRT-PCR. Immunohistochemistry analysis of HCC tissue microarray samples was used to identify the expression of NKG2D ligands. RESULTS In this study, NKG2D ligands expression in the mRNA and protein level was both abnormally expressed in HCC and associated with recurrence-free survival (RFS). Then, the recurrence-related variables of NKG2D ligands in HCC were selected by the multivariate Cox proportional hazards regression. Among the eight NKG2D ligands, MICA (HR = 1.347; 95% CI = 1.012-1.793; p = 0.041), ULBP3 (HR = 0.453; 95% CI = 0.231-0.889; p = 0.021) and ULBP5 (HR = 3.617; 95% CI = 1.819-7.194; p < 0.001) were significantly correlated with RFS in the TCGA-LIHC cohort. Then, the signature was constructed by the three NKG2D ligands. The predictive effectiveness of this signature was also validated in the OEP000321 dataset and Guilin cohort. Further, HCC patients were classified into low-risk and high-risk subgroups by the predictive score. Compared with the low-risk group, the high-risk group had poor RFS in both training and validation cohorts. Importantly, compared with the low-risk patients with the G1-G2 stage, the levels of infiltrated NK-activated cells and NKG2D expression were both lower in the high-risk patients. CONCLUSIONS The signature based on MICA, ULBP3, and ULBP5 could predict HCC recurrence.
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Affiliation(s)
- Dongbo Chen
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for liver Disease, Beijing, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
| | - Liying Ren
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for liver Disease, Beijing, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Pu Chen
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for liver Disease, Beijing, China
| | - Yao Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for liver Disease, Beijing, China
| | - Shaoping She
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for liver Disease, Beijing, China
| | - Yong Xie
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China
- Da Ren Biotech Limited, Hong Kong, China
| | - Weijia Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Hongsong Chen
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for liver Disease, Beijing, China
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19
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Inhibition of Checkpoint Kinase 1 (CHK1) Upregulates Interferon Regulatory Factor 1 (IRF1) to Promote Apoptosis and Activate Anti-Tumor Immunity via MICA in Hepatocellular Carcinoma (HCC). Cancers (Basel) 2023; 15:cancers15030850. [PMID: 36765808 PMCID: PMC9913340 DOI: 10.3390/cancers15030850] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND CHK1 is considered a key cell cycle checkpoint kinase in DNA damage response (DDR) pathway to communicate with several signaling pathways involved in the tumor microenvironment (TME) in numerous cancers. However, the mechanism of CHK1 signaling regulating TME in hepatocellular carcinoma (HCC) remains unclear. METHODS CHK1 expression in HCC tissue was determined by IHC staining assay. DNA damage and apoptosis in HCC cells induced by cisplatin or CHK1 inhibition were detected by WB and flow cytometry. The interaction of CHK1 and IRF1 was analyzed by single-cell RNA-sequence, WB, and immunoprecipitation assay. The mechanism of IRF1 regulating MICA was investigated by ChIP-qPCR. RESULTS CHK1 expression is upregulated in human HCC tumors compared to the background liver. High CHK1 mRNA level predicts advanced tumor stage and worse prognosis. Cisplatin and CHK1 inhibition augment cellular DNA damage and apoptosis. Overexpressed CHK1 suppresses IRF1 expression through proteolysis. Furthermore, single-cell RNA-sequence analyses confirmed that MICA expression positively correlated with IRF1 in HCC cells. Immunoprecipitation assay showed the binding between CHK1 and IRF1. Cisplatin and CHK1 inhibition upregulate MICA expression through IRF1-mediated transcriptional effects. A novel specific cis-acting IRF response element was identified at -1756 bp in the MICA promoter region that bound IRF1 to induce MICA gene transcription. MICA may increase NK cell and CD8+T cell infiltration in HCC. CONCLUSIONS DNA damage regulates the interaction of CHK1 and IRF1 to activate anti-tumor immunity via the IRF1-MICA pathway in HCC.
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20
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Yu L, Sun L, Liu X, Wang X, Yan H, Pu Q, Xie Y, Jiang Y, Du J, Yang Z. The imbalance between NKG2A and NKG2D expression is involved in NK cell immunosuppression and tumor progression of patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Res 2023; 53:417-431. [PMID: 36628564 DOI: 10.1111/hepr.13877] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 12/25/2022] [Accepted: 12/27/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Immunosuppression in a tumor microenvironment is associated with enhanced tumor progression. Natural killer group 2 (NKG2) family proteins, including inhibitory receptors and activators, can be used as attractive targets for immunotherapy of immune checkpoint inhibition. We further explore the expression level prognostic value of NKG2A and NKG2D in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). METHODS This study was a prospective study involving 92 patients with HBV-HCC, 16 patients with HBV-related liver cirrhosis, 18 patients with CHB, and 38 healthy donors. We analyzed the expression and related functions of NKG2A, NKG2D, and the NKG2A/NKG2D ratio in the peripheral blood of patients with HBV-HCC and analyzed tumor progression. The tissue samples from patients with HBV-HCC were further used for multiple immunofluorescence and immunohistochemistry. RESULTS In patients with HBV-HCC with tumor progression, the ratio of NKG2A/NKG2D is higher in NK cells and T cells. The Kaplan-Meier survival curve showed that the NKG2A/NKG2D ratio on NK cells could predict tumor progression in patients with HBV-HCC, and that an increase in this ratio was associated with inhibition of NK cell function. The Cancer Genome Atlas (TCGA) database was further used to verify that the higher the NKG2A/NKG2D ratio, the shorter the progression-free survival of patients with HCC, and the more likely the immune function was suppressed. CONCLUSIONS The imbalance between NKG2A and NKG2D of NK cells is involved in NK cell immunosuppression, and the increase of the NKG2A/NKG2D ratio is related to the tumor progression of HBV-HCC.
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Affiliation(s)
- Lihua Yu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lei Sun
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoli Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Qing Pu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuqing Xie
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuyong Jiang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Juan Du
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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21
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Fan J, Shi J, Zhang Y, Liu J, An C, Zhu H, Wu P, Hu W, Qin R, Yao D, Shou X, Xu Y, Tong Z, Wen X, Xu J, Zhang J, Fang W, Lou J, Yin W, Chen W. NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes. EMBO J 2022; 41:e107739. [PMID: 34913508 PMCID: PMC8762575 DOI: 10.15252/embj.2021107739] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 11/12/2022] Open
Abstract
Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti-tumor and anti-virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in-solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands still remain unclear. Using live-cell-based single-molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force-strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force-induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force-dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force-induced ligand conformational changes.
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Affiliation(s)
- Juan Fan
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiawei Shi
- Key Laboratory for Biomedical Engineering of the Ministry of EducationZhejiang UniversityHangzhouChina
| | - Yong Zhang
- Key Laboratory of RNA BiologyCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Junwei Liu
- Key Laboratory for Biomedical Engineering of the Ministry of EducationZhejiang UniversityHangzhouChina
- Department of Hepatobiliary and Pancreatic SurgeryThe Center for Integrated Oncology and Precision MedicineAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina
| | - Chenyi An
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Huaying Zhu
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Peng Wu
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Wei Hu
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Rui Qin
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Danmei Yao
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xin Shou
- Institute of Translational MedicineSchool of MedicineZhejiang UniversityHangzhouChina
| | - Yibing Xu
- Institute of Translational MedicineSchool of MedicineZhejiang UniversityHangzhouChina
| | - Zhou Tong
- Department of Medical OncologyFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Xue Wen
- Department of PathologyThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jianpo Xu
- Center for Stem Cell and Regenerative MedicineDepartment of Basic Medical SciencesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jin Zhang
- Center for Stem Cell and Regenerative MedicineDepartment of Basic Medical SciencesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Laboratory for Systems and Precision MedicineZhejiang University Medical CenterHangzhouChina
- Institute of HematologyZhejiang UniversityHangzhouChina
| | - Weijia Fang
- Department of Medical OncologyFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jizhong Lou
- Key Laboratory of RNA BiologyCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Weiwei Yin
- Key Laboratory for Biomedical Engineering of the Ministry of EducationZhejiang UniversityHangzhouChina
- Department of Thoracic SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness AppraisalCollege of Biomedical Engineering and Instrument of ScienceZhejiang UniversityHangzhouChina
| | - Wei Chen
- Department of Cell Biology and Department of Cardiology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory for Biomedical Engineering of the Ministry of EducationZhejiang UniversityHangzhouChina
- Department of Hepatobiliary and Pancreatic SurgeryThe Center for Integrated Oncology and Precision MedicineAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Laboratory for Systems and Precision MedicineZhejiang University Medical CenterHangzhouChina
- The MOE Frontier Science Center for Brain Science & Brain‐machine IntegrationZhejiang UniversityHangzhouChina
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22
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Chung A, Nasralla D, Quaglia A. Understanding the Immunoenvironment of Primary Liver Cancer: A Histopathology Perspective. J Hepatocell Carcinoma 2022; 9:1149-1169. [PMID: 36349146 PMCID: PMC9637345 DOI: 10.2147/jhc.s382310] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/01/2022] [Indexed: 11/26/2022] Open
Abstract
One of the most common cancers worldwide, primary liver cancer remains a major cause of cancer-related mortality. Hepatocellular carcinoma and cholangiocarcinoma represent the majority of primary liver cancer cases. Despite advances in the development of novel anti-cancer therapies that exploit targets within the immune system, survival rates from liver cancer remain poor. Furthermore, responses to immunotherapies, such as immune checkpoint inhibitors, have revealed limited and variable responses amongst patients with hepatocellular carcinoma, although combination immunotherapies have shown recent breakthroughs in clinical trials. This has shifted the focus towards improving our understanding of the underlying immune and molecular characteristics of liver tumours that may influence their response to immune-modulating treatments. In this review, we outline the complex interactions that occur in the tumour microenvironment of hepatocellular carcinoma and cholangiocarcinoma, respectively, from a histopathological perspective. We explore the potential role of a classification system based on immune-specific characteristics within each cancer type, the importance of understanding inter- and intra-tumoural heterogeneity and consider the future role of histopathology and novel technologies within this field.
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Affiliation(s)
- Annabelle Chung
- Department of Cellular Pathology, Royal Free Hospital, London, UK
| | - David Nasralla
- Department of Hepato-Pancreato-Biliary Surgery, Royal Free Hospital, London, UK
| | - Alberto Quaglia
- Department of Cellular Pathology, Royal Free Hospital, London, UK
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Abstract
Cancer is a leading cause of mortality worldwide, with around 10 million deaths every year. Despite huge advances due to immunotherapy, the majority of cancer patients present primary or secondary resistance to these treatments. In this Found in Translation, we focus on the approaches developed to harness the anti-tumor function of NK cells, suggesting promising strategies to complete the therapeutic arsenal of cancer immunotherapies.
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Affiliation(s)
- Laura Chiossone
- Innate Pharma Research Labs, Innate Pharma, Marseille, France
| | - Eric Vivier
- Innate Pharma Research Labs, Innate Pharma, Marseille, France
- Aix Marseille University, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'immunologie de Marseille-Luminy, Marseille, France
- Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Marseille-Immunopôle, Marseille, France
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24
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Mantovani S, Varchetta S, Mele D, Maiello R, Donadon M, Soldani C, Franceschini B, Torzilli G, Tartaglia G, Maestri M, Piccolo G, Barabino M, Opocher E, Bernuzzi S, Mondelli MU, Oliviero B. Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells. Cancers (Basel) 2022; 14:4060. [PMID: 36011052 PMCID: PMC9406989 DOI: 10.3390/cancers14164060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/10/2022] [Accepted: 08/18/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. METHODS Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. RESULTS sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. CONCLUSIONS We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance.
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Affiliation(s)
- Stefania Mantovani
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Stefania Varchetta
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Dalila Mele
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Roberta Maiello
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Cristiana Soldani
- Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Barbara Franceschini
- Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Giuseppe Tartaglia
- Division of General Surgery 1, Department of Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Marcello Maestri
- Division of General Surgery 1, Department of Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Gaetano Piccolo
- Unit of HepatoBilioPancreatic and Digestive Surgery, Department of Health Sciences, San Paolo Hospital, University of Milan, 20142 Milan, Italy
| | - Matteo Barabino
- Unit of HepatoBilioPancreatic and Digestive Surgery, Department of Health Sciences, San Paolo Hospital, University of Milan, 20142 Milan, Italy
| | - Enrico Opocher
- Unit of HepatoBilioPancreatic and Digestive Surgery, Department of Health Sciences, San Paolo Hospital, University of Milan, 20142 Milan, Italy
| | - Stefano Bernuzzi
- Immunohematology and Transfusion Service, Department of Diagnostic Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Mario U. Mondelli
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Barbara Oliviero
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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25
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Chen Y, Hu H, Yuan X, Fan X, Zhang C. Advances in Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma. Front Immunol 2022; 13:896752. [PMID: 35757756 PMCID: PMC9226303 DOI: 10.3389/fimmu.2022.896752] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/16/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is usually diagnosed in an advanced stage and has become the second deadliest type of cancer worldwide. The systemic treatment of advanced HCC has been a challenge, and for decades was limited to treatment with tyrosine kinase inhibitors (TKIs) until the application of immune checkpoint inhibitors (ICIs) became available. Due to drug resistance and unsatisfactory therapeutic effects of monotherapy with TKIs or ICIs, multi-ICIs, or the combination of ICIs with antiangiogenic drugs has become a novel strategy to treat advanced HCC. Antiangiogenic drugs mostly include TKIs (sorafenib, lenvatinib, regorafenib, cabozantinib and so on) and anti-vascular endothelial growth factor (VEGF), such as bevacizumab. Common ICIs include anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1), including nivolumab, pembrolizumab, durvalumab, and atezolizumab, and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab and ipilimumab. Combination therapies involving antiangiogenic drugs and ICIs or two ICIs may have a synergistic action and have shown greater efficacy in advanced HCC. In this review, we present an overview of the current knowledge and recent clinical developments in ICI-based combination therapies for advanced HCC and we provide an outlook on future prospects.
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Affiliation(s)
- Yue Chen
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Haoyue Hu
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and Technology, Chengdu, China
| | - Xianglei Yuan
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China
| | - Xue Fan
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Medicine School of University of Electronic Science and Technology, Chengdu, China
| | - Chengda Zhang
- Department of Gastroenterology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
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Xue JS, Ding ZN, Meng GX, Yan LJ, Liu H, Li HC, Yao SY, Tian BW, Dong ZR, Chen ZQ, Hong JG, Wang DX, Li T. The Prognostic Value of Natural Killer Cells and Their Receptors/Ligands in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Front Immunol 2022; 13:872353. [PMID: 35464489 PMCID: PMC9021421 DOI: 10.3389/fimmu.2022.872353] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/15/2022] [Indexed: 11/16/2022] Open
Abstract
Background Natural killer (NK) cells play major roles in eliminating tumor cells. Preliminary studies have shown that NK cells and their receptors/ligands have prognostic value in malignant tumors. However, the relevance of NK cells and their receptors/ligands level to the prognosis of hepatocellular carcinoma (HCC) remains unclear. Methods Several electronic databases were searched from database inception to November 8, 2021. Random effects were introduced to this meta-analysis. The relevance of NK cells and their receptors/ligands level to the prognosis of HCC was evaluated using hazard ratios (HRs) with 95% confidence interval (95%CI). Results 26 studies were included in the analysis. The pooled results showed that high NK cells levels were associated with better overall survival (HR=0.70, 95%CI 0.57–0.86, P=0.001) and disease-free survival (HR=0.61, 95%CI 0.40-0.93, P=0.022) of HCC patients. In subgroup analysis for overall survival, CD57+ NK cells (HR=0.70, 95%CI 0.55-0.89, P=0.004) had better prognostic value over CD56+ NK cells (HR=0.69, 95%CI 0.38-1.25, P=0.224), and intratumor NK cells had better prognostic value (HR=0.71, 95%CI 0.55-0.90, P=0.005) over peripheral NK cells (HR=0.66, 95%CI 0.41-1.06, P=0.088). In addition, high level of NK cell inhibitory receptors predicted increased recurrence of HCC, while the prognostic role of NK cell activating receptors remained unclear. Conclusion NK cells and their inhibitory receptors have prognostic value for HCC. The prognostic role of NK cell activating receptors is unclear and more high-quality prospective studies are essential to evaluate the prognostic value of NK cells and their receptors/ligands for HCC.
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Affiliation(s)
- Jun-Shuai Xue
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Guang-Xiao Meng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Hai-Chao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Sheng-Yu Yao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Jian-Guo Hong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.,Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
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Comprehensive Analysis of RAPGEF2 for Predicting Prognosis and Immunotherapy Response in Patients with Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:6560154. [PMID: 35518785 PMCID: PMC9064514 DOI: 10.1155/2022/6560154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 03/30/2022] [Indexed: 11/17/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is the sixth most common tumor worldwide. Additionally, deletion of RAPGEF2 plays a critical role in CNV and related to tumor immune microenvironment, whereas the prognostic potential of RAPGEF2 in HCC patient needs to be explored. Methods We looked for prognostic potential genes in HCC using a variety of R programs. Then, using the LASSO Cox regression, we thoroughly evaluated and integrated the RAPGEF2-related genes from TCGA database. Meanwhile, utilizing TCGA and ICGA databases, the link between RAPGEF2 and immunotherapy response in HCC was studied. In vivo, the effect of RAPGEF2 on tumor development and the capacity of natural killer (NK) cells to recruit were confirmed. To ascertain the connection between RAPGEF2-related genes and the prognosis of HCC, a prognostic model was created and validated. Result We demonstrated RAPGEF2 has a differential expression, and patients with deletion of RAPGEF2 gene get shorter survival in HCC. Additionally, the tissues without RAPGEF2 have a weaker ability to recruit the NK cells and response to immunotherapy. After that, we scoured the database for eight RAPGEF2-related genes linked with a better prognosis in HCC patients. Additionally, silencing RAPGEF2 accelerated tumor development in the HCC mouse model and decreased CD56+ NK cell recruitment in HCC tissues. TCGA database was used to classify patients into low- and high-risk categories based on the expression of related genes. Patients in the low-risk group had a significantly greater overall survival than those in the high-risk group (P < 0.001). Meanwhile, the low-risk group demonstrated connections with the NK cell and immunotherapy response. Finally, the prognostic nomogram showed a high sensitivity and specificity for predicting the survival of HCC patients at 1, 2, and 3 years. Conclusion The prognostic model based on RAPGEF2 and RAPGEF2-related genes showed an excellent predictive performance in terms of prognosis and immunotherapy response in HCC, therefore establishing a unique prognostic model for clinical assessment of HCC patients.
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28
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Sun S, Yu F, Xu D, Zheng H, Li M. EZH2, a prominent orchestrator of genetic and epigenetic regulation of solid tumor microenvironment and immunotherapy. Biochim Biophys Acta Rev Cancer 2022; 1877:188700. [PMID: 35217116 DOI: 10.1016/j.bbcan.2022.188700] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 02/15/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023]
Abstract
Immune checkpoint blockade (ICB) is regarded as a promising strategy for cancer therapy. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), has been implicated in the carcinogenesis of numerous solid tumors. However, the underlying mechanism of EZH2 in cancer immunotherapeutic resistance remains unknown. EZH2 orchestrates the regulation of the innate and adaptive immune systems of the tumor microenvironment (TME). Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. In this review, we summarized the dynamic functions of EZH2 on the different components of the TME, including tumor cells, T cells, macrophages, natural killer cells, myeloid-derived suppressor cells, dendritic cells, fibroblasts, and mesenchymal stem cells. Several ongoing anti-tumor clinical trials using EZH2 inhibitors have also been included as translational perspectives. In conclusion, based combinational therapy to enable ICB could offer a survival benefit in patients with cancer.
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Affiliation(s)
- Shanshan Sun
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Cancer Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Feng Yu
- Cancer Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Danying Xu
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Cancer Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Haiyan Zheng
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Min Li
- Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
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29
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Recent updates on chimeric antigen receptor T cell therapy for hepatocellular carcinoma. Cancer Gene Ther 2021; 28:1075-1087. [PMID: 33500535 DOI: 10.1038/s41417-020-00259-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 11/04/2020] [Accepted: 11/04/2020] [Indexed: 01/30/2023]
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables T cells to specifically recognize tumor-associated antigens through genetic engineering technology, thus exerting antitumor effects, and it has achieved encouraging outcomes in leukemia and lymphoma. Building on excellent progress, CAR-T therapy is also expected to work well in solid tumors. Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed at an advanced stage. Current management options for HCC remain limited, and although previous studies have indicated the feasibility of CAR-T cells, ideal therapeutic effects have not yet been achieved. This is, in part, due to the heterogeneity of tumor antigens, high intratumor pressure, immunosuppressive microenvironment, CAR-T cell exhaustion, and serious adverse reactions, which compromise the therapeutic efficiency of CAR-T immunotherapy in HCC. To overcoming these challenges, many ongoing preclinical and clinical studies were conducted. This review summarizes current CAR-T therapy targets in the treatment of HCC, discusses current obstacles and possible solutions in the process, and describes potential strategies to improve the efficacy of CAR-T cells for patients with HCC.
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Mattos ÂZ, Debes JD, Boonstra A, Vogel A, Mattos AA. Immune aspects of hepatocellular carcinoma: From immune markers for early detection to immunotherapy. World J Gastrointest Oncol 2021; 13:1132-1143. [PMID: 34616518 PMCID: PMC8465446 DOI: 10.4251/wjgo.v13.i9.1132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/02/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide. Most HCCs develop in an inflammatory microenvironment, and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis. In normal physiology, both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells, thus preventing the development of liver cancer. However, in the setting of impaired natural killer cells and exhaustion of T cells, HCC can develop. The immunogenic features of HCC have relevant clinical implications. There is a large number of immune markers currently being studied for the early detection of liver cancer, which would be critical in order to improve surveillance programs. Moreover, novel immunotherapies have recently been proven to be effective, and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC. It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy. The better we understand the immune aspects of HCC, the greater the benefit to patients through surveillance aiming for early detection of liver cancer, which allows for curative treatments, and, in cases of advanced disease, through the selection of the best possible therapy for each individual.
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Affiliation(s)
- Ângelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
| | - Jose D Debes
- Department of Medicine, Division of Gastroenterology and Infectious Diseases, University of Minnesota, Minneapolis, MN 55812, United States
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, The Netherlands
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, The Netherlands
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
| | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90020-090, Brazil
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Abstract
Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.
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Affiliation(s)
- Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Sandra Hervás-Stubbs
- Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
- Department of Immunology and Immunotherapy, Clinica Universidad de Navarra-IDISNA and CIBERONC, Pamplona, Spain
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Zhong X, Liao H, Hu S, Luo K, Zhu H. The diterpenoid adenanthin upregulates the expression of natural killer group 2D receptor ligands in hepatocellular carcinoma cells. Mol Cell Probes 2021; 59:101759. [PMID: 34265372 DOI: 10.1016/j.mcp.2021.101759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/20/2021] [Accepted: 07/08/2021] [Indexed: 12/09/2022]
Abstract
OBJECTIVE The natural killer (NK) group 2D (NKG2D) receptor plays a crucial role in NK cell-mediated anti-tumor immunity. NKG2D anti-proliferative effect is mediated by direct interactions of the receptor with its ligands that may be considered as a potential target for NK-based immunotherapeutic strategy in cancer cells. METHODS Here we report that a natural product adenanthin significantly promotes NKG2D ligands expression in hepatoma cells. The effect was determined using flow cytometry analysis. The activity of NK cell was evaluated by measuring its degranulation activity and cytotoxicity. RESULTS Our data indicates that the induction of NKG2D ligand binding to liver cancer cell surface receptors greatly improves the killing activity of NK cells against the cancer cells. CONCLUSIONS This is the first report of a new mechanism anti-cancer effects of adenanthin mediated by an indirect activation of NK cells. Our data suggests that adenanthin may be used to sensitize NK cells in tumor immunotherapy.
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Affiliation(s)
- Xiaoming Zhong
- Neonatal Intensive Care Unit, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341400, China
| | - Hongqun Liao
- Neonatal Intensive Care Unit, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341400, China
| | - Shaowen Hu
- College of Basic Medicine, Gannan Medical University, Ganzhou, 341400, China
| | - Kaiyuan Luo
- Neonatal Intensive Care Unit, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341400, China; Children's Medical Research Institute, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341400, China.
| | - Huifang Zhu
- Neonatal Intensive Care Unit, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341400, China; Children's Medical Research Institute, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341400, China.
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Granito A, Forgione A, Marinelli S, Renzulli M, Ielasi L, Sansone V, Benevento F, Piscaglia F, Tovoli F. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol 2021; 14:17562848211016959. [PMID: 34104211 PMCID: PMC8165525 DOI: 10.1177/17562848211016959] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib's efficacy in HCC that led to regorafenib's approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib's potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Via Albertoni 15, Bologna, 40138, Italy
- Division of Internal Medicine IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Vito Sansone
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
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Yuen VWH, Wong CCL. Hypoxia-inducible factors and innate immunity in liver cancer. J Clin Invest 2021; 130:5052-5062. [PMID: 32750043 DOI: 10.1172/jci137553] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The liver has strong innate immunity to counteract pathogens from the gastrointestinal tract. During the development of liver cancer, which is typically driven by chronic inflammation, the composition and biological roles of the innate immune cells are extensively altered. Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favors the recruitment and maintenance of pro-tumorigenic immune cells and the inhibition of anti-tumorigenic immune cells, promoting immune evasion. HIFs represent attractive therapeutic targets to inhibit the formation of an immunosuppressive microenvironment and growth of liver cancer.
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Affiliation(s)
| | - Carmen Chak-Lui Wong
- Department of Pathology and.,State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong, China
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Shi X, Li Q, Wang Y. Impact of regulatory T cells on the prognosis of hepatocellular carcinoma: A protocol for systematic review and meta analysis. Medicine (Baltimore) 2021; 100:e23957. [PMID: 33545975 PMCID: PMC7837976 DOI: 10.1097/md.0000000000023957] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 12/01/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND This meta-analysis aimed to systematically review current available literature to assess the impact of regulatory T cells (Tregs) on the prognosis of hepatocellular carcinoma (HCC). METHODS We will browse the online databases of PubMed and Cochrane Library. The summary hazard ratio (HR) and their 95% confidence intervals (CIs) will be combined to present the value reported in the study. CONCLUSION Our meta-analysis will provide useful guidance in treatment of HCC based on the reported evidences regarding the impact of Tregs on the prognosis of HCC. OSF REGISTRATION NUMBER 10.17605/OSF.IO/3Q8PW.
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Affiliation(s)
- Xinhui Shi
- Department of Medical Laboratory, Yancheng No.1 People's Hospital & Yancheng First Hospital Affiliated Hospital of Nanjing University Medical School
| | - Qisong Li
- College of Medical Technology, Jiangsu Vocational College of Medicine, Yancheng, P.R. China
| | - Yungang Wang
- Department of Medical Laboratory, Yancheng No.1 People's Hospital & Yancheng First Hospital Affiliated Hospital of Nanjing University Medical School
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36
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Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021; 18:525-543. [PMID: 33850328 PMCID: PMC8042636 DOI: 10.1038/s41575-021-00438-0] [Citation(s) in RCA: 828] [Impact Index Per Article: 207.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.
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Affiliation(s)
- Bruno Sangro
- grid.411730.00000 0001 2191 685XLiver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
| | - Pablo Sarobe
- grid.5924.a0000000419370271Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Sandra Hervás-Stubbs
- grid.5924.a0000000419370271Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain
| | - Ignacio Melero
- grid.5924.a0000000419370271Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain ,grid.411730.00000 0001 2191 685XDepartment of Immunology and Immunotherapy, Clinica Universidad de Navarra-IDISNA and CIBERONC, Pamplona, Spain
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Mantovani S, Varchetta S, Mele D, Donadon M, Torzilli G, Soldani C, Franceschini B, Porta C, Chiellino S, Pedrazzoli P, Santambrogio R, Barabino M, Cigala C, Piccolo G, Opocher E, Maestri M, Sangiovanni A, Bernuzzi S, Lhospice F, Kraiem M, Mondelli MU, Oliviero B. An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:3583. [PMID: 33266137 PMCID: PMC7761065 DOI: 10.3390/cancers12123583] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 12/29/2022] Open
Abstract
Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy.
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Affiliation(s)
- Stefania Mantovani
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Stefania Varchetta
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Dalila Mele
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Cristiana Soldani
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Barbara Franceschini
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Camillo Porta
- Department of Medical Sciences and Human Oncology, “Aldo Moro” University of Bari and Policlinico Consorziale, 70124 Bari, Italy;
| | - Silvia Chiellino
- Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.C.); (P.P.)
| | - Paolo Pedrazzoli
- Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.C.); (P.P.)
| | | | - Matteo Barabino
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Claudia Cigala
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Gaetano Piccolo
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Enrico Opocher
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Marcello Maestri
- Division of General Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, CRC “A. M. and A. Migliavacca” Center for Liver Disease, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Stefano Bernuzzi
- Immunohematology and Transfusion Service, Centre of Transplantation Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | | | - Manel Kraiem
- Innate Pharma, 13009 Marseille, France; (F.L.); (M.K.)
| | - Mario Umberto Mondelli
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Barbara Oliviero
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
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Easom NJW, Marks M, Jobe D, Gillmore R, Meyer T, Maini MK, Njie R. ULBP1 Is Elevated in Human Hepatocellular Carcinoma and Predicts Outcome. Front Oncol 2020; 10:971. [PMID: 32656081 PMCID: PMC7324784 DOI: 10.3389/fonc.2020.00971] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer death worldwide, and despite recent immunotherapeutic advances there remains a need for improved diagnostic, prognostic, and therapeutic tools. UL-16 binding protein 1 (ULBP1) is a ligand of the activatory receptor Natural Killer cell Group 2 receptor D (NKG2D) and is found as a cell-surface protein on some malignant cells including on human hepatocellular carcinomas. We aimed to explore the biological and clinical significance of NKG2D ligands in the circulation of patients with HCC. We measured ULBP1 in the serum of two retrospective cohorts of patients with HCC from the PROLIFICA cohort in The Gambia (n = 43) and from a tertiary care setting in the UK (n = 72) by sandwich ELISA. Exosome isolation by size exclusion was used to compare ULBP1 concentration in exosomes and as free protein. Survival analysis was performed and multiple linear regression and Poisson regression were used to assess the independent effect of ULBP1 concentration. ULBP1 was raised in both cohorts with HCC regardless of the underlying liver disease, and was not associated with markers of cirrhosis such as platelet count or serum albumin. ULBP1 was present predominantly as free protein rather than bound to exosomes. Serum ULBP1 > 2000 pg/ml was associated with a significantly reduced survival in both cohorts (hazard ratios in Gambian and UK cohorts 2.37 and 2.1, respectively). The effect remained significant after adjustment for BCLC staging (p = 0.03). These data suggest that ULBP1 merits further investigation as a prognostic marker in HCC in diverse settings and should also be explored as a therapeutic target.
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Affiliation(s)
- Nicholas J. W. Easom
- Division of Infection and Immunity, University College London, London, United Kingdom
- Hull University Teaching Hospitals NHS Trust, Castle Hill Hospital, Cottingham, United Kingdom
| | - Michael Marks
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Dawda Jobe
- MRC Unit the Gambia at LSHTM, Fajara, Gambia
| | | | - Tim Meyer
- Royal Free Hospital, London, United Kingdom
- Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom
| | - Mala K. Maini
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Ramou Njie
- Gambia Hepatitis Intervention Study (GHIS), IARC, Lyon, France
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Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment. J Hepatocell Carcinoma 2020; 7:45-76. [PMID: 32346535 PMCID: PMC7167284 DOI: 10.2147/jhc.s221187] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
- Department of Medicine, Division of Gastroenterology, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Kyle E Widmer
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
| | - Leela Nayak
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
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Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches. Cancers (Basel) 2020; 12:cancers12040926. [PMID: 32283827 PMCID: PMC7226319 DOI: 10.3390/cancers12040926] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.
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41
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Pinato DJ, Guerra N, Fessas P, Murphy R, Mineo T, Mauri FA, Mukherjee SK, Thursz M, Wong CN, Sharma R, Rimassa L. Immune-based therapies for hepatocellular carcinoma. Oncogene 2020; 39:3620-3637. [PMID: 32157213 PMCID: PMC7190571 DOI: 10.1038/s41388-020-1249-9] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 02/19/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.
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Affiliation(s)
- David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK.
| | - Nadia Guerra
- Department of Life Sciences, Imperial College London, South Kensington Campus, Exhibition Road, London, SW7 2AZ, UK
| | - Petros Fessas
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK
| | - Ravindhi Murphy
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK
| | | | - Francesco A Mauri
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK
| | - Sujit K Mukherjee
- Department of Metabolism, Digestion & Reproduction, Imperial College London, St. Mary's Hospital, Praed Street, London, UK
| | - Mark Thursz
- Department of Metabolism, Digestion & Reproduction, Imperial College London, St. Mary's Hospital, Praed Street, London, UK
| | - Ching Ngar Wong
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK
| | - Rohini Sharma
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W120HS, UK
| | - Lorenza Rimassa
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Via Manzoni 56, 20089, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 20090, Pieve Emanuele, Milan, Italy
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Bian J, He L, Wu Y, Liu W, Ma H, Sun M, Yu J, Yu Z, Wei M. Anterior gradient 2-derived peptide upregulates major histocompatibility complex class I-related chains A/B in hepatocellular carcinoma cells. Life Sci 2020; 246:117396. [PMID: 32035130 DOI: 10.1016/j.lfs.2020.117396] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/23/2020] [Accepted: 02/02/2020] [Indexed: 12/31/2022]
Abstract
AIMS Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Decrease in NKG2D ligand levels and exhaustion of NK cells in HCC patients are major causes of immune escape, high recurrence, poor prognosis, and low overall survival. Enhancing the susceptibility of HCC to NK cells by upregulating NKG2DLs on tumor cells is an effective treatment strategy. This study aimed to identify the effect of the Anterior gradient 2 (AGR2)-derived peptide P1, which was reported to bind to HLA-A*0201 as an epitope, on both the expression of major histocompatibility complex class I-related chains A/B (MICA/B) on HCC cells and the cytotoxicity of NK cells. MAIN METHODS The effect of P1 on MICA/B expression on HCC cells was determined by qRT-PCR, western blotting, and flow cytometry analysis. HCC cells were pre-treated with various pathway inhibitors to identify the molecular pathways associated with P1 treatment. The cytotoxicity of NK cells toward HCC was investigated by LDH cytotoxicity assay. The tumor-suppression effect of P1 was determined in vivo using a NOD/SCID mice HCC model. KEY FINDINGS P1 significantly increased MICA/B expression on HCC cells, thereby enhancing their susceptibility to the cytotoxicity of NK cells in vitro and in vivo. Further, p38 MAPK cell signaling pathway inhibitor SB203580 significantly attenuated the effects of P1 in vivo and in vitro. SIGNIFICANCE P1 upregulates MICA and MICB expression on HCC cells, thereby promoting their recognition and elimination by NK cells, which makes P1 an attractive novel immunotherapy agent.
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Affiliation(s)
- Jing Bian
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China
| | - Linxiu He
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China
| | - Yutong Wu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China
| | - Wensi Liu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China
| | - Heyao Ma
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China
| | - Mingli Sun
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China
| | - Jiankun Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China
| | - Zhaojin Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China..
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education; China Medical University, Shenyang, Liaoning Province, China..
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Tsilimigras DI, Ntanasis-Stathopoulos I, Moris D, Pawlik TM. Liver Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1296:227-241. [PMID: 34185296 DOI: 10.1007/978-3-030-59038-3_14] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The tumor microenvironment (TME) has recently been recognized as an important part of tumor development and growth. TME is a dynamic system orchestrated by immune, cancer and inflammatory cells, as well as the stromal tissue and surrounding extracellular matrix. While TME of primary hepatic tumors is usually characterized by a strong inflammatory background, the TME of liver metastases typically consists of otherwise healthy liver tissue. Chronic inflammation and hypoxia are key to the development and progression of primary liver cancer. The injury caused by chronic inflammation creates a condition of immune evasion that initiates a cascade of events that eventually leads to liver carcinogenesis.With liver metastases, primary tumors "prime" the target organs via secreting factors that induce expansion of myeloid cell populations and create a solid ground for successful cancer settlement. Once in the liver, metastatic cells begin a neovascularization process that is driven mainly by VEGF and FGF. Due to high mortality rates associated with liver cancer, as well as the limited effective treatment options for advanced disease, new therapies are urgently needed. Targeting a single molecule in a number of interactions between the tumor and the TME is highly unlikely to reduce tumor growth. Future trials should focus on combination therapies (i.e. targeted therapies combined with immunotherapy) to treat liver malignancies efficiently.
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Affiliation(s)
| | | | - Dimitrios Moris
- Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
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Clinicopathological relevance of tumor expression of NK group 2 member D ligands in resected non-small cell lung cancer. Oncotarget 2019; 10:6805-6815. [PMID: 31827723 PMCID: PMC6887580 DOI: 10.18632/oncotarget.27308] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 09/24/2019] [Indexed: 01/21/2023] Open
Abstract
UL16-binding protein (ULBP) 1-6 and MHC class I chain-related molecule A and B (MICA/B) are NK group 2, member D (NKG2D) ligands, which are specifically expressed in infected or transformed cells and are recognized by NK cells via NKG2D-NKG2D ligand interactions. We previously reported that MICA/B overexpression predicted improved clinical outcomes in patients with resected non-small cell lung cancer (NSCLC). However, the clinicopathological features and prognostic significance of ULBPs in NSCLC remain unclear. Here,ULBP1-6 expression was evaluated based on immunohistochemistry of 91 NSCLC samples from patients following radical surgery. ULBPs were expressed by the majority of NSCLC. Either ULBP1 or ULBP2/5/6 overexpression was associated with squamous-cell carcinoma histology, whereas ULBP4 overexpression was associated with younger age and adenocarcinoma histology. Although overexpression of ULBP1-6 did not impact clinical outcomes in NSCLC patients, integrative profiling with cluster analysis classified patients into 3 subgroups based on the expression pattern of NKG2D ligands. The subgroup characterized by ULBP1 or ULBP2/5/6 high expressing but ULBP4 low expressing tumors showed poor overall survival. Taken together with previous results, NSCLC histological subtype strongly correlates with NKG2D ligands expression pattern. NKG2D ligands expression levels assessed by multiple immune parameters could predict clinical outcomes of patients with NSCLC.
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Wu M, Mei F, Liu W, Jiang J. Comprehensive characterization of tumor infiltrating natural killer cells and clinical significance in hepatocellular carcinoma based on gene expression profiles. Biomed Pharmacother 2019; 121:109637. [PMID: 31810126 DOI: 10.1016/j.biopha.2019.109637] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/30/2019] [Accepted: 10/31/2019] [Indexed: 02/06/2023] Open
Abstract
Natural Killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance, however, the specific mechanism in hepatocellular carcinoma (HCC) has not been well understood. In the present study, we estimated the relative abundances of NK cells in HCC using gene expression data, and found that NK cell abundance was lower in HCC tissues than in the adjacent normal tissues. With the common HCC subclasses, we also found that three HCC subclasses had distinct abundances of NK cells. Moreover, we also found strong association between NK cell abundances and genes encoding immune checkpoint proteins, such as KLRD1, CD96, TIGIT, CD86, HAVCR2, PDCD1 (PD-1), HLA-E, CD274 (PD-L1), and CTLA4, among which, KLRD1 vs. HLA-E, CD274 vs. PDCD1, and CTLA4 vs. CD86 were three pairs of receptors and ligands. Furthermore, we investigated the clinical significance of NK cell activities in HCC, and found that the NK cell abundances were highly associated with the response to sorafinib, and higher NK cell abundances may prolong both the recurrence-free and overall survival of HCC patients. In summary, the present study not only improved our understanding of the potential tumor immune evasion mechanism of NK cells in HCC, but also proposed the potential clinical application of NK activities in HCC treatment and risk assessment.
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Affiliation(s)
- Mei Wu
- Department of Gastroenterology, the First People's Hospital of Jingmen, Jingmen, Hubei, China
| | - Fang Mei
- Department of Cardiology, the First People's Hospital of Jingmen, Jingmen, Hubei, China
| | - Weishuo Liu
- Department of Pathology of the First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Jianwei Jiang
- Department of General Surgery, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China.
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46
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Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res 2019; 38:396. [PMID: 31500650 PMCID: PMC6734524 DOI: 10.1186/s13046-019-1396-4] [Citation(s) in RCA: 298] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.
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MESH Headings
- Adaptive Immunity
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Biomarkers, Tumor
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Clinical Trials as Topic
- Combined Modality Therapy/methods
- Humans
- Immunity, Innate
- Immunotherapy/adverse effects
- Immunotherapy/methods
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Translational Research, Biomedical
- Treatment Outcome
- Tumor Microenvironment/immunology
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Affiliation(s)
- Yaojie Fu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shanshan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
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Sun B, Yang D, Dai H, Liu X, Jia R, Cui X, Li W, Cai C, Xu J, Zhao X. Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells. Cancer Immunol Res 2019; 7:1813-1823. [PMID: 31484657 DOI: 10.1158/2326-6066.cir-19-0026] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 06/01/2019] [Accepted: 08/29/2019] [Indexed: 02/05/2023]
Abstract
Despite the great success of chimeric antigen receptor T (CAR-T)-cell therapy in the treatment of hematologic malignancies, CAR-T-cell therapy is limited in solid tumors, including hepatocellular carcinoma (HCC). NK group 2 member D (NKG2D) ligands (NKG2DL) are generally absent on the surface of normal cells but are overexpressed on malignant cells, offering good targets for CAR-T therapy. Indeed, analysis of The Cancer Genome Atlas and HCC tumor samples showed that the expression of most NKG2DLs was elevated in tumors compared with normal tissues. Thus, we designed a novel NKG2D-based CAR comprising the extracellular domain of human NKG2D, 4-1BB, and CD3ζ signaling domains (BBz). NKG2D-BBz CAR-T cells efficiently killed the HCC cell lines SMMC-7721 and MHCC97H in vitro, which express high levels of NKG2DLs, whereas they less efficiently killed NKG2DL-silenced SMMC-7721 cells or NKG2DL-negative Hep3B cells. Overexpression of MICA or ULBP2 in Hep3B improved the killing capacity of NKG2D-BBz CAR-T cells. T cells expressing the NKG2D-BBz CAR effectively eradicated SMMC-7721 HCC xenografts. Collectively, these results suggested that NKG2D-BBz CAR-T cells could potently eliminate NKG2DL-high HCC cells both in vitro and in vivo, thereby providing a promising therapeutic intervention for patients with NKG2DL-positive HCC.
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Affiliation(s)
- Bin Sun
- Laboratory of Animal Tumor Models, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.,Nanjing Kaedi Biotech Co. Ltd., Nanjing, Jiangsu, China
| | - Dong Yang
- Laboratory of Animal Tumor Models, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.,Nanjing Kaedi Biotech Co. Ltd., Nanjing, Jiangsu, China
| | - Hongjiu Dai
- Nanjing Kaedi Biotech Co. Ltd., Nanjing, Jiangsu, China.
| | - Xiuyun Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Ru Jia
- Department of GI Oncology, the 307 Hospital of Academy of Military Medical Science, Beijing, China
| | - Xiaoyue Cui
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.,Department of Gastroenterology, The Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Wenxuan Li
- College of Life Sciences, Sichuan University, Chengdu, Sichuan, China
| | - Changchun Cai
- Department of Gastroenterology, The Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Jianming Xu
- Department of GI Oncology, the 307 Hospital of Academy of Military Medical Science, Beijing, China
| | - Xudong Zhao
- Laboratory of Animal Tumor Models, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. .,Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.,Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
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48
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Cariani E, Missale G. Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications. Liver Int 2019; 39:1608-1621. [PMID: 31314948 DOI: 10.1111/liv.14192] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/02/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023]
Abstract
The development of immunotherapy for solid tumours has boosted interest in the contexture of tumour immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumour cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high-resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response and possibly new therapeutic targets. Here, we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies.
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Affiliation(s)
- Elisabetta Cariani
- Toxicology and Advanced Diagnostics, Ospedale S. Agostino-Estense, Modena, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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Parvifoline AA Promotes Susceptibility of Hepatocarcinoma to Natural Killer Cell-Mediated Cytolysis by Targeting Peroxiredoxin. Cell Chem Biol 2019; 26:1122-1132.e6. [DOI: 10.1016/j.chembiol.2019.04.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/24/2019] [Accepted: 04/02/2019] [Indexed: 12/23/2022]
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50
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Johnston MP, Khakoo SI. Immunotherapy for hepatocellular carcinoma: Current and future. World J Gastroenterol 2019; 25:2977-2989. [PMID: 31293335 PMCID: PMC6603808 DOI: 10.3748/wjg.v25.i24.2977] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/24/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.
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Affiliation(s)
- Michael P Johnston
- Department of Hepatology, Southampton General Hospital, University Hospital Southampton, Southampton SO16 6YD, United Kingdom
| | - Salim I Khakoo
- Department of Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, United Kingdom
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