Associating transcriptomics data with inflammatory markers to understand tumour microenvironment in hepatocellular carcinoma

Abstract

Background Liver cancer is the fourth leading cause of cancer‐related death globally which is estimated to reach more than 1 million deaths a year by 2030. Among liver cancer types, hepatocellular carcinoma (HCC) accounts for approximately 90% of the cases and is known to have a tumour promoting inflammation regardless of its underlying aetiology. However, current promising treatment approaches, such as immunotherapy, are partially effective for most of the patients due to the immunosuppressive nature of the tumour microenvironment (TME). Therefore, there is an urgent need to fully understand TME in HCC and discover new immune markers to eliminate resistance to immunotherapy. Methods We analyse three microarray datasets, using unsupervised and supervised methods, in an effort to discover signature genes. First, univariate, and multivariate, feature selection methods, such as the Boruta algorithm, are applied. Subsequently, an optimisation procedure, which utilises random forest algorithm with three dataset pairs combinations, is performed. The resulting optimal gene sets are then combined and further subjected to network analysis and pathway enrichment analysis so as to obtain information related to their biological relevance. The microarray datasets were analysed via the MCP‐counter, CIBERSORT, TIMER, EPIC, and quanTIseq deconvolution methods and an estimation of cell type abundances for each dataset sample were identified. The differences in the cell type abundances, between the adjacent and tumour sample groups, were then assessed using a Wilcoxon Rank Sum test ( p ‐value < 0.05). Results The optimal gene signature sets, derived from each of the data pairs combination, achieved AUC values ranging from 0.959 to 0.988 in external validation sets using Random Forest model. CLEC1B and PTTG1 genes are retrieved across each optimal set. Among the signature genes, PTTG1, AURKA, and UBE2C genes are found to be involved in the regulation of mitotic sister chromatid separation and anaphase‐promoting complex (APC) dependent catabolic process (adjusted p ‐value < 0.001). Additionally, the application of deconvolution algorithms revealed significant changes in cell type abundances of Regulatory T (Treg) cells, M0 and M1 macrophages, and T CD8 + cells between adjacent and tumour samples. Conclusion We identified ECM1 gene as a potential immune‐related marker acting through immune cell migration and macrophage polarisation. Our results indicate that macrophages, such as M0 macrophage and M1 macrophage cells, undergo significant changes in HCC TME. Moreover, our immune deconvolution approach revealed significant infiltration of Treg cells and M0 macrophages, and a significant decrease in T CD8 + cells and M1 macrophages in tumour samples.

Tumor-derived colorectal cancer organoids induce a unique Treg cell population through direct modulation of CD4+T cell differentiation

“…High TGM2 expression in gastric or pancreatic cancer is associated to increased Treg cells presence and a worse prognosis 43,44 . PTTG1 expression is found in immunosuppressive Treg cells in triple-negative breast cancer and associated with significant Treg cell infiltration in liver tumors 45,46 . Additionally, high expression of FIBP correlates with elevated frequency of Treg cells in acute myeloid leukemia, serving as a prognostic biomarker indicating a poor prognosis 47 .…”

“…From this pool, we extracted the 56 most significantly DEGs (p≤0.01) (Suppl. Figure 4a), including Tgm2, Pttg1, and Fibp, which have been associated with TI-Treg cells in the TME of other cancers [43][44][45][46][47] . To delineate the biological processes associated with the 1155 DEGs, we conducted a pathway analysis (Suppl.…”

Development of a novel tumor microenvironment-related radiogenomics model for prognosis prediction in hepatocellular carcinoma

“…The long-term prognosis of patients with HCC still remains dismal ( 2 ). Molecular marker-based classification schemes for HCC have not been routinely applied, which greatly limits accurate treatment and prognosis prediction ( 3 , 4 ). Hence, it is essential to integrate multiomics factors for valuable biomarker acquisition, as this can provide a multidimensional basis for the selection of therapeutic options.…”