Predictive value of hypoxia, metabolism and immune factors for prognosis in hepatocellular carcinoma: a retrospective analysis and multicenter validation study

Abstract

The tumor microenvironment (TME), as a potent and pervasive factor of tumorigenesis and tumor progression, has a profound impact on the clinical outcomes of hepatocellular carcinoma (HCC). A systematic analysis of TME factors in HCC is still lacking and urgently needed. In this retrospective analysis and multicenter validation study, a total of 987 HCC patients with RNA-seq or microarray data and the corresponding clinical information from five cohorts were included. A TME risk score was developed based on five factors (hypoxia, nucleotide, TCA cycle, T helper cells and activated CD8 T cells). We also identified various types of clinical parameters and molecular features associated with the TME risk score. The TME risk factor network depicts close associations among the factors. Our TME risk score could be a practical and reliable predictor that can stratify patients according to distinct clinical outcomes and was validated by integrating five HCC patient cohorts (HR= 2.27, 95% CI: 1.79-2.86, P<0.001). Pan-cancer analysis also suggested that the prognostic signature was an effective prognostic indicator in 9,122 patients across 30 types of cancer. Correlation analysis revealed that the TME risk score was significantly associated with tumor progression-related clinical factors and molecular factors. TME factors are perturbations in HCC patients, and these alterations are vital determinants of both clinical outcomes and biological characteristics. The TME risk score we proposed is valuable for deciphering the molecular characteristics of the TME in HCC and is an effective prognostic predictor for HCC prognosis evaluation.

Prognostic significance of exportin-5 in hepatocellular carcinoma

“…Additionally, we explored the correlation between XPO5 and various immune cells to uncover its intricate connection with immune modulation in HCC. Our findings generally align with the literature, indicating a positive correlation between high TME scores and better HCC prognosis despite the mixed results in database studies regarding tumor mutation burden and TME scores[ 25 - 27 ]. We also investigated the impact of the expression of specific genes, including XPO5, on drug responsiveness in HCC.…”

Identification of key pathways, genes and immune cell infiltration in hypoxia of high-altitude acclimatization via meta-analysis and integrated bioinformatics analysis

“…A hypoxic environment increases inflammation to expedite pathogen clearance by modulating the immune response (Dominguez-Gutierrez et al, 2014). Angiogenesis, metabolism rewiring, and immunomodulatory molecules are all activated by hypoxia (Lin et al, 2020). Considering that the subjects in the GSE46480 dataset developed acute high altitude sickness after arrival at high altitude, and immune infiltration analysis showed significant differences, we think that the oxygen-deprived environment at high altitudes will, therefore, alter the functionality of infiltrated immune cell populations.…”

Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets

“… 6 , 7 Malignant cell differentiation, proliferation, invasion, metastasis, and even medication therapy resistance is influenced by the interplay between malignant cells and the immediate environment influences, affecting how a tumor progresses. 6 , 8 Recent research has demonstrated that epigenetics regulates immune cell activation and infiltration into TME, which may alter immunotherapy efficacy. 9 , 10 Therefore, epigenetic alterations are potential tumor immunotherapy targets that can be employed in conjunction with treatments such as immune checkpoint inhibitors (ICIs) to significantly improve tumor patient survival and quality of life.…”