Tumor Microenvironment in Hepatocellular Carcinoma: Key Players for Immunotherapy

Feng, Hai; Zhuo, Yunhui; Zhang, Xuemei; Li, Yuyao; Li, Yue; Duan, Xiangjuan; Song, Jia; Xu, Cheng; Gao, Yueqiu; Yu, Zhuo

doi:10.2147/jhc.s381764

Cited by 13 publications

(13 citation statements)

References 149 publications

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“…In addition to the direct killing of tumour cells, polarized macrophages also act as antigen‐presenting cells in adaptive immunity, as we proved in the animal model. It is well known that tumour cells escape immune surveillance because TAMs (M2) have poor antigen presentation ability and inhibit the immune response of T cells by releasing immunosuppressive factors 41 . Recently, some studies on TAM‐targeted cancer therapy have focused on the following strategies: inhibiting the recruitment of macrophages, transforming tumour‐promoting M2 macrophages into antitumour M1 macrophages and inhibiting the survival of TAMs 42 .…”

Section: Discussionmentioning

confidence: 99%

“…Data are presented as the mean ± SEM from three independent experiments. *p < 0.05; **p < 0.01, and n.s., no significance.antigen presentation ability and inhibit the immune response of T cells by releasing immunosuppressive factors 41. Recently, some studies on TAM-targeted cancer therapy have focused on the following strategies: inhibiting the recruitment of macrophages, transforming tumour-promoting M2 macrophages into antitumour M1 macrophages and inhibiting the survival of TAMs 42.…”

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confidence: 99%

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Irreversible repolarization of tumour‐associated macrophages by low‐Pi stress inhibits the progression of hepatocellular carcinoma

Liao

et al. 2023

J Cellular Molecular Medi

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Numerous studies have shown the positive correlation between high levels of Pi and tumour progression. A critical goal of macrophage‐based cancer therapeutics is to reduce anti‐inflammatory macrophages (M2) and increase proinflammatory antitumour macrophages (M1). This study aimed to investigate the relationship between macrophage polarization and low‐Pi stress. First, the spatial populations of M2 and M1 macrophages in 22 HCC patient specimens were quantified and correlated with the local Pi concentration. The levels of M2 and M1 macrophage markers expressed in the peritumour area were higher than the intratumour levels, and the expression of M2 markers was positively correlated with Pi concentration. Next, monocytes differentiated from THP‐1 cells were polarized against different Pi concentrations to investigate the activation or silencing of the expression of p65, IκB‐α and STAT3 as well as their phosphorylation. Results showed that low‐Pi stress irreversibly repolarizes tumour‐associated macrophages (TAMs) towards the M1 phenotype by silencing stat6 and activating p65. Moreover, HepG‐2 and SMCC‐7721 cells were cultured in conditioned medium to investigate the innate anticancer immune effects on tumour progression. Both cancer cell lines showed reduced proliferation, migration and invasion, as epithelial–mesenchymal transition (EMT) was inactivated. In vivo therapeutic effect on the innate and adaptive immune processes was validated in a subcutaneous liver cancer model by the intratumoural injection of sevelamer. Tumour growth was significantly inhibited by the partial deprivation of intratumoural Pi as the tumour microenvironment under low‐Pi stress is more immunostimulatory. The anticancer immune response, activated by low‐Pi stress, suggests a new macrophage‐based immunotherapeutic modality.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Irreversible repolarization of tumour‐associated macrophages by low‐Pi stress inhibits the progression of hepatocellular carcinoma

Liao

et al. 2023

J Cellular Molecular Medi

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“…However, HCC progression is a complex multifactorial process involving the accumulation of different types of damage, complex signal transduction, and heterogeneity. [34][35][36] Therefore, exploring the key molecules and mechanisms involved in the occurrence and development of HCC is necessary to improve the effectiveness of diagnosis and treatment.…”

Section: Discussionmentioning

confidence: 99%

FNBP4 is a Potential Biomarker Associated with Cuproptosis and Promotes Tumor Progression in Hepatocellular Carcinoma

Zheng¹,

Zhang²,

Wu³

et al. 2023

IJGM

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Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors that lacks an efficient therapeutic approach because of its elusive molecular mechanisms. This study aimed to investigate the biological function and potential mechanism of formin-binding protein 4 (FNBP4) in HCC. Methods FNBP4 expression in tissues and cells were detected by quantitative real-time PCR (qRT‒PCR), Western blot, and immunohistochemistry (IHC). The Kaplan-Meier method was used to explore the correlation between the FNBP4 expression and clinical survival. MTT, EdU incorporation, colony formation, and Transwell assays were performed to evaluate the function of FNBP4 in cell proliferation and migration in vitro. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to explore the potential mechanism of FNBP4. The prognostic risk signature and nomogram were constructed to demonstrate the prognostic value of FNBP4. Results We found that FNBP4 was upregulated in patients with HCC and associated with poor overall survival (OS). Furthermore, knockdown of FNBP4 inhibited the proliferation and migration in HCC cells. Then, we performed a KEGG pathway analysis of the coexpressed genes associated with FNBP4 and found that FNBP4 may be associated with tumor-related signaling pathways and cuproptosis. We verified that FNBP4 could cause cell cycle progression and inactivation of the hippo signaling pathway. A prognostic risk signature containing three FNBP4-related differentially expressed cuproptosis regulators (DECRs) was established and can be used as an independent risk factor to evaluate the prognosis of patients with HCC. In addition, a nomogram including a risk score and clinicopathological factors was used to predict patient survival probabilities. Conclusion FNBP4, as a potential biomarker associated with cuproptosis, promotes HCC cell proliferation and metastasis. We provide a new potential strategy for HCC treatment by targeting FNBP4.

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“…HCC is a common malignancy and is the second most common cause of tumor-related death worldwide, having caused hundreds of thousands of deaths in 2020 [21] . In the HCC tumor microenvironment, immune suppression and tumor escape can be caused by regulatory T cells (Tregs), bone marrow-derived suppressor cells (MDSC), and some cytokines, which contribute to the development and progression of HCC [22][23][24] . Immune checkpoint inhibitor(ICI) therapy plays an anti-tumor role by restoring the normal function of immunologically active cells and re-establishing tumor-speci c immunity.…”

Section: Discussionmentioning

confidence: 99%

Cancer Stem Cells Remodel the Tumor Microenvironment and Influence Immunotherapy Response in Hepatocellular Carcinoma

Zhang

Yang

Zhuang

et al. 2023

Preprint

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Background: Cancer stem cells are the important factors that lead to drug resistance, recurrence and metastasis of tumor. Immunotherapy has become the first-line treatment for advanced Hepatocellular Carcinoma(HCC), however, the importance of cancer stem cells in the immunotherapy of HCC has not been well elucidated. Methods: We identified a subset of cells with stemness characteristics by analyzing single-cell sequencing data from tumor tissue samples from 10 patients with HCC. We screened these cell populations for overexpressed genes, defined as cancer stem cell-related genes. Subsequently, we comprehensively analyzed the bulk RNA sequencing data of 365 HCC patients to construct a cancer stem cell-related genes prognostic signature(CSGPS). According to the CSGPS, 365 patients with HCC were divided into high-risk and low-risk groups. Multiple independent external cohorts were used to assess the predictive value of the CSGPS. T cell receptor (TCR) richness, Cancer Testicular Antigens (CTA) scores, Microsatellite instability (MSI), expression of immune checkpoint-related genes, and Tumour Immune Dysfunction and Exclusion (TIDE) scores were used to assess the intensity of response to immunotherapy in different risk groups. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression levels of cancer stem cell-related genes in HCC tissues. Results: CSGPS is an independent risk factor for the prognosis of HCC patients, and it is significantly superior to other clinical features in predicting the prognosis and immunotherapy response of HCC patients. Multiple independent external cohorts validated the validity and robustness of the CSGPS. Immune infiltration analysis showed that cancer stem cell-related genes can recruit immune cells with immunosuppressive functions, such as Treg, macrophages infiltration. The CSGPS was correlated with the TCR, CTA score, MSI score, expression of immune checkpoint-related genes, and TIDE score. Patients in the high-risk group identified by the CSGPS may respond more strongly to immunotherapy and be more suitable to immunotherapy. The results of qRT-PCR confirmed that 8 cancer stem cell-related genes were overexpressed in HCC tissues. Conclusion: Cancer stem cell-related genes are overexpressed in HCC and contribute to the formation of an immunosuppressive microenvironment. Targeting cancer stem cells may become a new target for immunotherapy of HCC. Our novel prognostic signatureof cancer stem cell-related genes can effectively predict the prognosis and immunotherapy response of HCC patients. In the future, the prognostic signature will help clinicians to select the appropriate population for immunotherapy and improve the response rate of immunotherapy.

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Tumor Microenvironment in Hepatocellular Carcinoma: Key Players for Immunotherapy

Cited by 13 publications

References 149 publications

Irreversible repolarization of tumour‐associated macrophages by low‐Pi stress inhibits the progression of hepatocellular carcinoma

Irreversible repolarization of tumour‐associated macrophages by low‐Pi stress inhibits the progression of hepatocellular carcinoma

FNBP4 is a Potential Biomarker Associated with Cuproptosis and Promotes Tumor Progression in Hepatocellular Carcinoma

Cancer Stem Cells Remodel the Tumor Microenvironment and Influence Immunotherapy Response in Hepatocellular Carcinoma

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