Comprehensive analysis of prognostic immune-related genes in the tumor microenvironment of hepatocellular carcinoma (HCC)

Abstract Background Hepatocellular carcinoma (HCC) is one of the most prevalent and inflammation-associated cancers. The tumor microenvironment (TME) plays an essential role in HCC development and metastasis, leading to poor prognosis. The overall TME immune cells infiltration characterizations mediated by immune-related genes (IRGs) remain unclear. In this study, we aimed to investigate whether immune-related genes could be indicators for the prognosis of HCC patients and TME cell infiltration characterization as well as responses to immunotherapy. Methods We obtained differentially expressed immune-related genes (DE IRGs) between normal liver tissues and liver cancer tissues from The Cancer Genome Atlas (TCGA) database. To identify the prognostic genes and establish an immune risk signature, we performed univariable Cox regression survival analysis and the Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the DE IRGs by robust rank aggregation method. Cox regression analysis was used to identify independent prognostic factors in HCC. We estimated the immune cell infiltration in TME via CIBERSORT and immunotherapy response through TIDE algorithm. Results We constructed an immune signature and validated its predictive capability. The immune signature included 7 differentially expressed IRGs: BIRC5, CACYBP, NR0B1, RAET1E, S100A8, SPINK5, and SPP1. The univariate and multivariate cox analysis showed that the 7-IRGs signature was a robust independent prognostic factor in the overall survival of HCC patients. The 7-IRG signature was associated with some clinical features, including gender, vascular invasion, histological grade, clinical stage, T stage. We also found that the 7-IRG signature could reflect the infiltration characterization of different immunocytes in the tumor microenvironment (TME) and had a good correlation with immune checkpoint molecules, revealing that the poor prognosis might be partly due to immunosuppressive TME. The Tumour Immune Dysfunction and Exclusion (TIDE) analysis data showed that the 7-IRG signature had great potential for indicating the immunotherapy response in HCC patients. The mutation analysis demonstrated a significant difference in the tumor mutation burden (TMB) between the high- and low-risk groups, partially explaining this signature's predictive value. Conclusion In a word, we constructed and validated a novel, immune-related prognostic signature for HCC patients. This signature could effectively indicate HCC patients' survival and immunotherapy response. And it might act as potential immunotherapeutic targets for HCC patients.

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Comprehensive analysis of prognostic immune‑related genes associated with the tumor microenvironment of pancreatic ductal adenocarcinoma

Oncology Letters ◽

10.3892/ol.2020.12228 ◽

2020 ◽

Vol 20 (6) ◽

pp. 1-1

Author(s):

Shibai Yan ◽

Juntao Fang ◽

Yuanqiang Zhu ◽

Yong Xie ◽

Feng Fang

Keyword(s):

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Comprehensive Analysis ◽

Ductal Adenocarcinoma ◽

Immune Related Genes

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Status and Development of The Tumor Microenvironment in Hepatocellular Carcinoma*

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS ◽

10.3724/sp.j.1206.2011.00383 ◽

2012 ◽

Vol 39 (5) ◽

pp. 416-422

Author(s):

Zhi-Lei LIU ◽

Wei SUN ◽

Fu-Chu HE ◽

Xian-Ling CONG ◽

Ying JIANG

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment

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Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment

Molecules ◽

10.3390/molecules26051343 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1343

Author(s):

Gagan Chhabra ◽

Chandra K. Singh ◽

Deeba Amiri ◽

Neha Akula ◽

Nihal Ahmad

Keyword(s):

Tumor Microenvironment ◽

Immune Cell ◽

Cancer Therapies ◽

Regulatory Cells ◽

Immunomodulatory Effects ◽

Cancer Management ◽

Natural Agents ◽

Anticancer Effects ◽

Cancer Types ◽

Immune Related Genes

Immunomodulation of the tumor microenvironment is emerging as an important area of research for the treatment of cancer patients. Several synthetic and natural agents are being investigated for their ability to enhance the immunogenic responses of immune cells present in the tumor microenvironment to impede tumor cell growth and dissemination. Among them, resveratrol, a stilbenoid found in red grapes and many other natural sources, has been studied extensively. Importantly, resveratrol has been shown to possess activity against various human diseases, including cancer. Mechanistically, resveratrol has been shown to regulate an array of signaling pathways and processes involving oxidative stress, inflammation, apoptosis, and several anticancer effects. Furthermore, recent research suggests that resveratrol can regulate various cellular signaling events including immune cell regulation, cytokines/chemokines secretion, and the expression of several other immune-related genes. In this review, we have summarized recent findings on resveratrol’s effects on immune regulatory cells and associated signaling in various cancer types. Numerous immunomodulatory effects of resveratrol suggest it may be useful in combination with other cancer therapies including immunotherapy for effective cancer management.

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Is the Rationale of Anatomical Liver Resection for Hepatocellular Carcinoma Universally Adoptable? A Hypothesis-Driven Review

Medicina ◽

10.3390/medicina57020131 ◽

2021 ◽

Vol 57 (2) ◽

pp. 131

Author(s):

Young-Jen Lin ◽

Cheng-Maw Ho

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Surgical Resection ◽

Tumor Recurrence ◽

Hepatic Metastases ◽

Vascular Supply ◽

Tumor Ablation ◽

Supporting Evidence ◽

En Bloc ◽

Margin Width

Surgical resection is the first-line curative treatment modality for resectable hepatocellular carcinoma (HCC). Anatomical resection (AR), described as systematic removal of a liver segment confined by tumor-bearing portal tributaries, may improve survival by reducing the risk of tumor recurrence compared with non-AR. In this article, we propose the rationale for AR and its universal adoption by providing supporting evidence from the advanced understanding of a tumor microenvironment and accumulating clinical experiences of locoregional tumor ablation therapeutics. AR may be advantageous because it completely removes the en-bloc by interrupting tumor vascular supply and thus extirpates the spreading of tumor microthrombi, if they ever exist, within the supplying portal vein. However, HCC is a hypervascular tumor that can promote neoangiogenesis in the local tumor microenvironment, which in itself can break through the anatomical boundary within the liver and even retrieve nourishment from extrahepatic vessels, such as inferior phrenic or omental arteries. Additionally, increasing clinical evidence for locoregional tumor ablation therapies, such as radiofrequency ablation, predominantly performed as a non-anatomical approach, suggests comparable outcomes for surgical resection, particularly in small HCC and colorectal, hepatic metastases. Moreover, liver transplantation for HCC, which can be considered as AR of the whole liver followed by implantation of a new graft, is not universally free from post-transplant tumor recurrence. Overall, AR should not be considered the gold standard among all surgical resection methods. Surgical resection is fundamentally reliant on choosing the optimal margin width to achieve en-bloc tumor niche removal while balancing between oncological radicality and the preservation of postoperative liver function. The importance of this is to liberate surgical resilience in hepatocellular carcinoma. The overall success of HCC treatment is determined by the clearance of the theoretical niche. Developing biomolecular-guided navigation device/technologies may provide surgical guidance toward the total removal of microscopic tumor niche to achieve superior oncological outcomes.

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Metabolic reprogramming of immune cells: Shaping the tumor microenvironment in hepatocellular carcinoma

Cancer Medicine ◽

10.1002/cam4.4177 ◽

2021 ◽

Author(s):

Yujia Xia ◽

Zachary J. Brown ◽

Hai Huang ◽

Allan Tsung

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Immune Cells ◽

Metabolic Reprogramming

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New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

Journal of Personalized Medicine ◽

10.3390/jpm11030219 ◽

2021 ◽

Vol 11 (3) ◽

pp. 219

Author(s):

Ya-Ling Yang ◽

Yen-Hsiang Chang ◽

Chia-Jung Li ◽

Ying-Hsien Huang ◽

Ming-Chao Tsai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Crucial Role ◽

Human Cancer ◽

Metabolic Adaptation ◽

Advanced Hcc ◽

Diagnosis And Prognosis ◽

Competitive Endogenous Rnas ◽

Growing Body

Hepatocellular carcinoma (HCC) remains one of the most lethal human cancer globally. For advanced HCC, curable plan for advanced HCC is yet to be established, and the prognosis remains poor. The detail mechanisms underlying the progression of HCC tumorigenicity and the corruption of tumor microenvironment (TME) is complex and inconclusive. A growing body of studies demonstrate microRNAs (miRs) are important regulators in the tumorigenicity and TME development. Notably, mounting evidences indicate miR-29a play a crucial role in exerting hepatoprotective effect on various types of stress and involved in the progression of HCC, which elucidates their potential theragnostic implications. In this review, we reviewed the advanced insights into the detail mechanisms by which miR-29a dictates carcinogenesis, epigenetic program, and metabolic adaptation, and implicated in the sponging activity of competitive endogenous RNAs (ceRNA) and the TME components in the scenario of HCC. Furthermore, we highlighted its clinical significance in diagnosis and prognosis, as well as the emerging therapeutics centered on the activation of miR-29a.

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