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Multi-omics study revealing the complexity and spatial heterogeneity of tumor-infiltrating lymphocytes in primary liver carcinoma.

ABSTRACT: Intratumoral heterogeneity has been revealed in primary liver carcinoma (PLC). However, spatial heterogeneity of tumor-infiltrating lymphocytes (TILs), which reflects one dimension of a tumor's spatial heterogeneity, and the relationship between TIL diversity, local immune response and mutation burden remain unexplored in PLC. Therefore, we performed immune repertoire sequencing, gene expression profiling analysis and whole-exome sequencing in parallel on five regions of each tumor and on matched adjacent normal tissues and peripheral blood from five PLC patients. A significantly higher cumulative frequency of the top 250 most abundant TIL clones was observed in tumors than in peripheral blood. Besides, overlap rates of T cell receptor (TCR) repertoire for intratumor comparisons, significant higher than those for tumor-adjacent normal tissue comparisons and tumor-blood comparisons, which provide evidence for antigen-driven clonal expansion in PLC. Analysis of the percentage of ubiquitous TCR sequences, regional frequencies of each clone and TIL diversity suggested TIL clones varying between distinct regions of the same tumor, which indicated weak TCR repertoire similarity within a single tumor. Furthermore, correlation analysis revealed that TIL diversity significantly correlated with the expression of immune response genes rather than the mutation load. We conclude that intratumoural T-cell clones are spatially heterogeneous, which can lead to underestimate the immune profile of PLC from a single biopsy sample and may present challenge to adoptive cell therapy using autologous TILs. TIL diversity provides a reasonable explanation for the degree of immune response, implied TIL diversity can serve as a surrogate marker to monitor the effect of immunotherapy.

SUBMITTER: Shi L

PROVIDER: S-EPMC5471016 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Multi-omics study revealing the complexity and spatial heterogeneity of tumor-infiltrating lymphocytes in primary liver carcinoma.

Shi Lijun L Zhang Yang Y Feng Lin L Wang Liming L Rong Weiqi W Wu Fan F Wu Jianxiong J Zhang Kaitai K Cheng Shujun S

Oncotarget 20170501 21

Intratumoral heterogeneity has been revealed in primary liver carcinoma (PLC). However, spatial heterogeneity of tumor-infiltrating lymphocytes (TILs), which reflects one dimension of a tumor's spatial heterogeneity, and the relationship between TIL diversity, local immune response and mutation burden remain unexplored in PLC. Therefore, we performed immune repertoire sequencing, gene expression profiling analysis and whole-exome sequencing in parallel on five regions of each tumor and on matche ...[more]

PMID: 28422742

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Project description:Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene-metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene-metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.

Dataset Information

Multi-omics study revealing the complexity and spatial heterogeneity of tumor-infiltrating lymphocytes in primary liver carcinoma.

Publications

Multi-omics study revealing the complexity and spatial heterogeneity of tumor-infiltrating lymphocytes in primary liver carcinoma.

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