Immunotherapies for hepatocellular carcinoma

Llovet, Josep M.; Castet, Florian; Heikenwälder, Mathias; Maini, Mala K.; Mazzaferro, Vincenzo; Pinato, David J.; Pikarsky, Eli; Zhu, Andrew X.; Finn, Richard S.

doi:10.1038/s41571-021-00573-2

Cited by 928 publications

(826 citation statements)

References 205 publications

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“…The elements and enrichment of immune cells in the tumor microenvironment can forcefully influence tumor progression and the effectiveness of immunotherapy. 4 However, elucidating the complex tumor-immune interactions poses significant computational and experimental challenges. 22 Given the gene expression profiles of more than 10,000 samples in the TCGA database, the TIMER database provides a systematic analysis of tumor-infiltrating immune cells (TIICs) for 32 cancer types with a user-friendly portal.…”

Section: Methodsmentioning

confidence: 99%

“… 3 For unresectable HCC, several targeted therapeutic agents, such as Sorafenib and regorafenib, have been approved for HCC treatment. 4 The overall therapeutic effect of these drugs is not satisfactory due to their side effects and drug resistance. 4 Therefore, novel and reliable diagnostic and therapeutic markers for HCC are urgently needed to improve patient prognosis.…”

Section: Introductionmentioning

confidence: 99%

“… 4 The overall therapeutic effect of these drugs is not satisfactory due to their side effects and drug resistance. 4 Therefore, novel and reliable diagnostic and therapeutic markers for HCC are urgently needed to improve patient prognosis. 5 …”

Section: Introductionmentioning

confidence: 99%

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Insights into the Association Between QSER1 and M2 Macrophages and Remarkable Malignancy Characteristics in Hepatocellular Carcinoma

Wu¹,

Shi²,

Duan³

et al. 2022

IJGM

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Purpose Glutamine and serine rich 1 (QSER1), as a DNA methylation modulator, play a crucial role in transforming tumor cells. Previous studies have shown that QSER1 plays a role in regulating the progression of various malignancies and that QSER1 dysfunction is connected with precancerous lesions of hepatocellular carcinoma (HCC) as well as HCC prognosis. However, little is known about the detailed contribution of QSER1 in HCC. Patients and Methods Various statistical methods such as Kaplan–Meier method, AUC analysis, GSEA, and immune-infiltration analysis were used to evaluate the relationship between QSER1 expression and clinical features, prognostic factors, and potential functional mechanisms of QSER1. Results QSER1 expression was negatively correlated with clinicopathological features (clinical stage, pathological grade, TP53 mutation, lymph node metastasis) and clinical outcome (overall survival versus recurrence). Functional enrichment analysis further suggested that QSER1 is involved in multiple pathways related to DNA replication and tumor immunity. TIMER analysis indicated that high QSER1 expression was significantly associated with higher macrophage infiltration and poorer macrophage-related outcomes. In particular, QSER1 was significantly more associated with M2 macrophages than M1 macrophages. Conclusion Overall, elevated QSER1 is a potential prognostic marker for HCC and is associated with immune infiltration in HCC.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insights into the Association Between QSER1 and M2 Macrophages and Remarkable Malignancy Characteristics in Hepatocellular Carcinoma

Wu¹,

Shi²,

Duan³

et al. 2022

IJGM

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“…The macrotrabecular/compact pattern, a pathological feature of the Hoshida S2 subclass, was associated with the activation of the oncogenes for YAP/TAZ and stemness markers EpCAM, CK19, and SALL4. The immune status of this subclass has been reported to elevate CCL5, abundant TIL, immunosuppressive receptors expression, enhanced IFNγ signaling and strong antigen presentation [ 56 ]. We believe that this subclass corresponds exactly to the Hyde phenotype, which is an immune microenvironment with high affinity for ICI treatment.…”

Section: Compatibility With Previous Molecular Classifications Of Hcc and Development Of Anticancer Drugsmentioning

confidence: 99%

Clinical Significance of the Duality of Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma

Aoki

Nishida

Kudo

2022

Cancers

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Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors has been approved as a first-line treatment for unresectable hepatocellular carcinoma (HCC), indicating a critical role of ICIs in the treatment of HCC. However, 20% of patients do not respond effectively to ICIs; mutations in the activation of the Wnt/β-catenin pathway are known to contribute to primary resistance to ICIs. From this point of view, non-invasive detection of Wnt/β-catenin activation should be informative for the management of advanced HCC. Wnt/β-catenin mutations in HCC have a dual aspect, which results in two distinct tumor phenotypes. HCC with minimal vascular invasion, metastasis, and good prognosis is named the “Jekyll phenotype”, while the poorly differentiated HCC subset with frequent vascular invasion and metastasis, cancer stem cell features, and high serum Alpha fetoprotein levels, is named the “Hyde phenotype”. To differentiate these two HCC phenotypes, a combination of the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and fluoro-2-deoxy-D-glucose-PET/CT may be useful. The former is applicable for the detection of the Jekyll phenotype, as nodules present higher enhancement on the hepatobiliary phase, while the latter is likely to be informative for the detection of the Hyde phenotype by showing an increased glucose uptake.

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“…Hepatocellular carcinoma (HCC) ranks as the second cause of cancer-related deaths worldwide [1]. Major risk factors, including infection with hepatitis B and C viruses, alcohol consumption, aflatoxin contamination, and selective expression of oncogenes, contribute significantly to hepatocarcinogenesis [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma

Che

et al. 2022

Cancers

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Mitochondria are highly dynamic organelles and undergo constant fission and fusion, which are both essential for the maintenance of cell physiological functions. Dysregulation of dynamin-related protein 1 (Drp1)-dependent mitochondrial dynamics is associated with tumorigenesis and the chemotherapeutic response in hepatocellular carcinoma (HCC). The enzyme cyclooxygenase-2 (COX-2) is overexpressed in most cancer types and correlates with a poor prognosis. However, the roles played by the translocation of mitochondrial COX-2 (mito-COX-2) and the interaction between mito-COX-2 and Drp1 in chemotherapeutic responses remain to be elucidated in the context of HCC. Bioinformatics analysis, paired HCC patient specimens, xenograft nude mice, immunofluorescence, transmission electron microscopy, molecular docking, CRISPR/Cas9 gene editing, proximity ligation assay, cytoplasmic and mitochondrial fractions, mitochondrial immunoprecipitation assay, and flow cytometry analysis were performed to evaluate the underlying mechanism of how mito-COX-2 and p-Drp1Ser616 interaction regulates the chemotherapeutic response via mitochondrial dynamics in vitro and in vivo. We found that COX-2 and Drp1 were frequently upregulated and confer a poor prognosis in HCC. We also found that the proportion of mito-COX-2 and p-Drp1Ser616 was increased in HCC cell lines. In vitro, we demonstrated that the enhanced mitochondrial translocation of COX-2 promotes its interaction with p-Drp1Ser616 via PTEN-induced putative kinase 1 (PINK1)-mediated Drp1 phosphorylation activation. This increase was associated with higher colony formation, cell proliferation, and mitochondrial fission. These findings were confirmed by knocking down COX-2 in HCC cells using CRISPR/Cas9 technology. Furthermore, inhibition of Drp1 using pharmacologic inhibitors (Mdivi-1) or RNA interference (siDNM1L) decreased mito-COX-2/p-Drp1Ser616 interaction-mediated mitochondrial fission, and increased apoptosis in HCC cells treated with platinum drugs. Moreover, inhibiting mito-COX-2 acetylation with the natural phytochemical resveratrol resulted in reducing cell proliferation and mitochondrial fission, occurring through upregulation of mitochondrial deacetylase sirtuin 3 (SIRT3), which, in turn, increased the chemosensitivity of HCC to platinum drugs in vitro and in vivo. Our results suggest that targeting interventions to PINK1-mediated mito-COX-2/p-Drp1Ser616-dependent mitochondrial dynamics increases the chemosensitivity of HCC and might help us to understand how to use the SIRT3-modulated mito-COX-2/p-Drp1Ser616 signaling axis to develop an effective clinical intervention in hepatocarcinogenesis.

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Immunotherapies for hepatocellular carcinoma

Cited by 928 publications

References 205 publications

Insights into the Association Between QSER1 and M2 Macrophages and Remarkable Malignancy Characteristics in Hepatocellular Carcinoma

Insights into the Association Between QSER1 and M2 Macrophages and Remarkable Malignancy Characteristics in Hepatocellular Carcinoma

Clinical Significance of the Duality of Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma

Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma

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