Abstract

BackgroundHepatocellular 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.MethodsWe 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.ResultsWe 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.ConclusionIn 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.

Highlights

  • Hepatocellular carcinoma (HCC) is one of the most prevalent and inflammation-associated cancers

  • 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. It might act as potential immunotherapeutic targets for HCC patients

  • Identification of HCC differentially expressed immune‐related genes Based on the adjusted P-value < 0.05 and | log2 |> 1, we obtained 8996 differentially expressed genes (DEGs) in the The Cancer Genome Atlas (TCGA) dataset: 7444 genes were up-regulated and 1552 downregulated

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Summary

Introduction

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. 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. Hepatocellular carcinoma (HCC), with 42,810 cases diagnosed and 30,160 deaths in the United States in 2020 [1], is the sixth most widespread neoplasm and the third leading cause of cancer death [2]. The incidence of HCC is gradually increasing, and liver cirrhosis is the leading cause of death. Most HCC patients in China are infected with the hepatitis B virus, indicating that HCC patients perhaps be suitable for immunotherapy

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