Hypoxia Molecular Characterization in Hepatocellular Carcinoma Identifies One Risk Signature and Two Nomograms for Clinical Management

Abstract

Hypoxia is a universal feature in the tumor microenvironment (TME). Nonetheless, the heterogeneous hypoxia patterns of TME have still not been elucidated in hepatocellular carcinoma (HCC). Using consensus clustering algorithm and public datasets, we identified heterogeneous hypoxia subtypes. We also revealed the specific biological and clinical characteristics via bioinformatic methods. The principal component analysis algorithm was employed to develop a hypoxia-associated risk score (HARS). We identified the two hypoxia subtypes: low hypoxia pattern (C1) and high hypoxia pattern (C2). C1 was less sensitive to immunotherapy compared to C2, consistent with the lack of immune cells and immune checkpoints (ICPs) in C1, whereas C2 was the opposite. C2 displayed worse prognosis and higher sensitivity to obatoclax relative to C1, while C1 was more sensitive to sorafenib. The two subtypes also demonstrated subtype-specific genomic variations including mutation, copy number alteration, and methylation. Moreover, we developed and validated a risk signature: HARS, which had excellent performance for predicting prognosis and immunotherapy. We revealed two hypoxia subtypes with distinct biological and clinical characteristics in HCC, which enhanced the understanding of hypoxia pattern. The risk signature was a promising biomarker for predicting prognosis and immunotherapy.

CELF2 is a candidate prognostic and immunotherapy biomarker in triple‐negative breast cancer and lung squamous cell carcinoma: A pan‐cancer analysis

“…While ICIs target the interactions between immune and tumour cells within the TME, certain alterations that occur in the TME can also affect the responsiveness to immunotherapy 3 . Recent studies have confirmed that key biological processes such as autophagy, hypoxia and ferroptosis, as well as some molecular alterations, can contribute to the immunotherapeutic efficacy and prognosis of cancer patients by affecting the distributions and interactions of distinct immune cell subsets in the TME 10–13 . To date, there are still few cancer patients who can benefit from immunotherapy, and thus, it is essential to explore additional therapeutic targets.…”

Tumor hypoxia: an important regulator of tumor progression or a potential modulator of tumor immunogenicity?

“… 37 In one study on primary soft tissue sarcoma, the concurrent application of a hypoxia signature and a signature measuring the degree of genomic instability revealed a significant enrichment of hypoxic tumors in the group classified as having high genomic instability. 38 The positive correlation between hypoxia and TMB has been further validated in independent studies for hepatocellular carcinoma, 39 gastric cancer 40 and pancreatic cancer. 41 In gastric cancer, TMB positivity was further correlated with higher positive rate of ERO1A protein, a marker of hypoxia, in 73 tumors tested by immunohistochemistry.…”

Immune checkpoint molecules are regulated by transforming growth factor (TGF)-β1-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma

“…Despite the approval of few ICIs and several ongoing clinical trials, ICIs as a monotherapy have failed to show promising result as first-line treatment in HCC compared to Sorafenib 53 , 54 . In addition, the response of HCC patients to ICIs may be affected by several molecular features including genetic alterations, variation in inflammatory infiltrates, microsatellite instability (MSI) and expression of alternative immune checkpoint molecules 53 , 55 , 56 . Thus, there is a need for identification of robust predictive biomarkers along with combined ICI therapeutic approaches for enhanced clinical outcome in HCC patients 53 .…”

“…The HCC TME includes cancer cells, immune cells [T-cells, B-cells, dendritic cells, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs)], carcinoma-associated fibroblasts, endothelial cells, hepatic stellate cells, and the extracellular matrix (ECM) 65 . As the TME is a crucial facilitator of HCC progression and resistance to immunotherapies, much of the recent research is focused on the various components of the TME to identify predictive and prognostic biomarkers for ICI treatment in HCC patients 56 , 66 . For instance, a study developed a prognostic biomarker for immunotherapy comprising of eight gene risk signature based on hypoxia status in the TME of HCC patient 56 .…”

“…As the TME is a crucial facilitator of HCC progression and resistance to immunotherapies, much of the recent research is focused on the various components of the TME to identify predictive and prognostic biomarkers for ICI treatment in HCC patients 56 , 66 . For instance, a study developed a prognostic biomarker for immunotherapy comprising of eight gene risk signature based on hypoxia status in the TME of HCC patient 56 . Another study reported CD38 expression within the TME including tumour and certain immune subsets, such as macrophages as a predictive marker of responsiveness to anti-PD-1/PD-L1 single agent treatment in HCC patients 66 .…”