Role of Immunity in Pathogenesis and Treatment of Hepatocellular Carcinoma

Schmidt, Nathalie M.; Thimme, Robert

doi:10.1159/000444558

Cited by 17 publications

(10 citation statements)

References 86 publications

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“…Most research into tumor immunology, including in the setting of the liver, has focused on understanding, and attempting to reverse, defects in CD8 T cells ( 3 ). However, NK cells also have potent capacity to recognize and kill tumor cells ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction

et al. 2018

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NK cells have potent antitumor capacity. They are enriched in the human liver, with a large subset specialized for tissue-residence. The potential for liver-resident versus liver-infiltrating NK cells to populate, and exert antitumor functions in, human liver tumors has not been studied. We examined liver-resident and liver-infiltrating NK cells directly ex vivo from human hepatocellular carcinomas (HCCs) and liver colorectal (CRC) metastases, compared with matched uninvolved liver tissue. We found that NK cells were highly prevalent in both HCC and liver CRC metastases, although at lower frequencies than unaffected liver. Up to 79% of intratumoral NK cells had the CXCR6+CD69+ liver-resident phenotype. Direct ex vivo staining showed that liver-resident NK cells had increased NKG2D expression compared to their non-resident counterparts, but both subsets had NKG2D downregulation within liver tumors compared to uninvolved liver. Proliferation of intratumoral NK cells (identified by Ki67) was selectively impaired in those with the most marked NKG2D downregulation. Human liver tumor NK cells were functionally impaired, with reduced capacity for cytotoxicity and production of cytokines, even when compared to the hypo-functional tissue-resident NK cells in unaffected liver. Coculture of human liver NK cells with the human hepatoma cell line PLC/PRF/5, or with autologous HCC, recapitulated the defects observed in NK cells extracted from tumors, with downmodulation of NKG2D, cytokine production, and target cell cytotoxicity. Transwells and conditioned media confirmed a requirement for cell contact with PLC/PRF/5 to impose NK cell inhibition. IL-15 was able to recover antitumor functionality in NK cells inhibited by in vitro exposure to HCC cell lines or extracted directly from HCC. In summary, our data suggest that the impaired antitumor function of local NK cells reflects a combination of the tolerogenic features inherent to liver-resident NK cells together with additional contact-dependent inhibition imposed by HCC itself. The demonstration that IL-15 can recover hepatic NK cell function following tumor exposure supports its inclusion in immunotherapy strategies.

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Section: Introductionmentioning

confidence: 99%

IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction

et al. 2018

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“…The immune system is thought to be a decisive factor in the development of cancer [9,10], including HCC. Immune cells are major components of the tumor microenvironment and play a role in many key steps of HCC development from tumor growth to the development of metastasis [11,12]. Besides, a large amount of inflammatory mediators were found to be associated with HCC development.…”

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confidence: 99%

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

et al. 2020

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Background: Growing evidence has suggested that immune-related genes play crucial roles in the development and progression of hepatocellular carcinoma (HCC). Nevertheless, the utility of immune-related genes for evaluating the prognosis of HCC patients are still lacking. The study aimed to explore gene signatures and prognostic values of immune-related genes in HCC. Methods:We comprehensively integrated gene expression data acquired from 374 HCC and 50 normal tissues in The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) analysis and univariate Cox regression analysis were performed to identify DEGs that related to overall survival. An immune prognostic model was constructed using the Lasso and multivariate Cox regression analyses. Furthermore, Cox regression analysis was applied to identify independent prognostic factors in HCC. The correlation analysis between immune-related signature and immune cells infiltration were also investigated. Finally, the signature was validated in an external independent dataset.Results: A total of 329 differentially expressed immune-related genes were detected. 64 immune-related genes were identified to be markedly related to overall survival in HCC patients using univariate Cox regression analysis. Then we established a TF-mediated network for exploring the regulatory mechanisms of these genes. Lasso and multivariate Cox regression analyses were applied to construct the immune-based prognostic model, which consisted of nine immune-related genes. Further analysis indicated that this immune-related prognostic model could be an independent prognostic indicator after adjusting to other clinical factors. The relationships between the risk score model and immune cell infiltration suggested that the nine-gene signature could reflect the status of tumor immune microenvironment. The prognostic value of this nine-gene prognostic model was further successfully validated in an independent database.Conclusions: Together, our study screened potential prognostic immune-related genes and established a novel immune-based prognostic model of HCC, which not only provides new potential prognostic biomarkers and therapeutic targets, but also deepens our understanding of tumor immune microenvironment status and lays a theoretical foundation for immunotherapy.

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“…17 Moreover, tumor growth favors this dysregulation, which is already present in HCC patients. 18 The ability of tumor cells to evade the immune system is a key for transformation of non-tumor cells into malignant cells. 19 The immune cells and tumor cells interact through a dynamic process known as immunoediting, which has three phases: 1) the elimination phase, in which…”

Section: Mechanisms Of Immune Tolerance and Suppression Of Hccmentioning

confidence: 99%

Recent Advances and Future Directions in Immunotherapeutics for Hepatocellular Carcinoma

2019

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Systemic target therapeutic drugs, such as sorafenib, lenvatinib, or regorafenib are the only drugs that are known to be effective against advanced hepatocellular carcinoma (HCC). However, these agents show a limited efficacy in killing residual tumors. Immunotherapy is an alternative approach to this treatment and has been used to successfully treat different cancers, including HCC. HCC is an inflammation-induced cancer and represents a very interesting target for immunotherapeutics. Immunotherapies aim to reverse the immune tolerance and suppression found in tumor microenvironments and include approaches, such as adoptive cell therapy, immune checkpoint inhibition, and cancer vaccination. Adoptive cell therapy uses autologous natural killer or cytokine-induced killer cells by cultivating them ex vivo and subsequently reinfusing them into the patient. Immune checkpoint inhibitors reactivate tumorspecific T cells by suppressing checkpoint-mediated inhibitory signaling. Cancer vaccination induces a tumor-specific immune response by activating effector T lymphocytes. A wide range of potential immunotherapy-related adverse events occur; therefore, a multidisciplinary collaborative management is required across the clinical spectrum. This review summarizes the current status of immunotherapy for HCC and provides a perspective on its future applications.

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Role of Immunity in Pathogenesis and Treatment of Hepatocellular Carcinoma

Cited by 17 publications

References 86 publications

IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction

IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

Recent Advances and Future Directions in Immunotherapeutics for Hepatocellular Carcinoma

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