Abstract
Background: Generally, hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion. Hypoxia can impact intercellular crosstalk in the tumor microenvironment. This study aimed to explore and elucidate the underlying relationship between hypoxia and immunotherapy in patients with HCC.Methods: HCC genomic and clinicopathological datasets were obtained from The Cancer Genome Atlas (TCGA-LIHC), Gene Expression Omnibus databases (GSE14520) and International Cancer Genome Consortium (ICGC-LIRI). The TCGA-LIHC cases were divided into clusters based on single sample gene set enrichment analysis and hierarchical clustering. After identifying patients with immunosuppressive microenvironment with different hypoxic conditions, correlations between immunological characteristics and hypoxia clusters were investigated. Subsequently, a hypoxia-associated score was established by differential expression, univariable Cox regression, and lasso regression analyses. The score was verified by survival and receiver operating characteristic curve analyses. The GSE14520 cohort was used to validate the findings of immune cell infiltration and immune checkpoints expression, while the ICGC-LIRI cohort was employed to verify the hypoxia-associated score.Results: We identified hypoxic patients with immunosuppressive HCC. This cluster exhibited higher immune cell infiltration and immune checkpoint expression in the TCGA cohort, while similar significant differences were observed in the GEO cohort. The hypoxia-associated score was composed of five genes (ephrin A3, dihydropyrimidinase like 4, solute carrier family 2 member 5, stanniocalcin 2, and lysyl oxidase). In both two cohorts, survival analysis revealed significant differences between the high-risk and low-risk groups. In addition, compared to other clinical parameters, the established score had the highest predictive performance at both 3 and 5 years in two cohorts.Conclusion: This study provides further evidence of the link between hypoxic signals in patients and immunosuppression in HCC. Defining hypoxia-associated HCC subtypes may help reveal potential regulatory mechanisms between hypoxia and the immunosuppressive microenvironment, and our hypoxia-associated score could exhibit potential implications for future predictive models.
Highlights
As the major subtype of liver cancer, hepatocellular carcinoma (HCC) is diagnosed in more than half a million people worldwide each year [1]
Our results indicate that the presence of tumor microenvironment (TME) hypoxia is a potential biomarker of HCC immunotherapeutic response and prognosis
Three independent cohorts (TCGA-LIHC, GSE14520, and International Cancer Genome Consortium (ICGC)-LIRI) were employed in our research, with the The Cancer Genome Atlas (TCGA)-LIHC cohort used as a training dataset and the other two cohorts used as a validation dataset
Summary
As the major subtype of liver cancer, hepatocellular carcinoma (HCC) is diagnosed in more than half a million people worldwide each year [1]. For HCC, immunohistochemical scoring of CD38 molecule in the TME can be used to predict responsiveness to antiprogrammed cell death 1/CD274 molecule (i.e., anti-PD-1/PDL1) immunotherapy [9]. A TME-based risk score was shown to be an effective prognostic predictor for HCC [10]. The HCC TME is complex, with diverse populations of innate and adaptive immune cells that influence tumor immune evasion and the response to immunotherapy [11]. It is necessary to explore and elucidate the roles of intrinsic cellular factors and extrinsic factors in patients with immunosuppressive HCC TME. Hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion.
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