Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas

Abstract

ObjectiveHepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice.DesignWe harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings.ResultsTumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis.ConclusionThere is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.

Tumor microenvironment characterization identifies two lung adenocarcinoma subtypes with specific immune and metabolic state

“…The immune repressed TME cluster B showed an enrichment in the TCA cycle. A recently published study indicates that immunosuppressive and immunodeficient hepatocellular carcinomas show increased activity of the citrate cycle (TCA cycle) and nucleotide biosynthesis 43 . The TCA cycle is a classic and complicated energy metabolism cycle that involves many intermediates.…”

Identification and validation of an immune-related prognostic signature for hepatocellular carcinoma

“…Thus far, there is no established personal treatment strategy for HCC patients. Individual risk assessment might be an essential step for the successful implementation of personal treatment strategies [19,20].…”

High‐dimensional single‐cell proteomics analysis reveals the landscape of immune cells and stem‐like cells in renal tumors

“…Zhang et al studied the heterogeneity of the immune microenvironment in hepatocellular carcinoma (HCC) using MC and identified three different HCC subtypes with immunocompetent, immunodeficient, and immunosuppressed characteristics, respectively, by clustering immune cells in the HCC microenvironment. This classification can be used to evaluate the prognosis of patients with HCC and to provide theoretical support for the choice of treatment . Currently, there is little knowledge about the role of heterogeneity in the development of renal tumors due to the limitations in the research methods.…”

“…Currently, single‐cell profiling is an important means to elucidate tumor heterogeneity, and the main methods involved in this are single‐cell sequencing and cytology. These methods allow analysis of multiple markers in a single tumor cell that have been isolated from fresh or fixed primary and metastatic tumors . Single‐cell RNA sequencing provides high‐dimensional, single‐cell data .…”