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Comprehensive analysis of the association between tumor glycolysis and immune/inflammation function in breast cancer.

ABSTRACT: BACKGROUND:Metabolic reprogramming, immune evasion and tumor-promoting inflammation are three hallmarks of cancer that provide new perspectives for understanding the biology of cancer. We aimed to figure out the relationship of tumor glycolysis and immune/inflammation function in the context of breast cancer, which is significant for deeper understanding of the biology, treatment and prognosis of breast cancer. METHODS:Using mRNA transcriptome data, tumor-infiltrating lymphocytes (TILs) maps based on digitized H&E-stained images and clinical information of breast cancer from The Cancer Genome Atlas projects (TCGA), we explored the expression and prognostic implications of glycolysis-related genes, as well as the enrichment scores and dual role of different immune/inflammation cells in the tumor microenvironment. The relationship between glycolysis activity and immune/inflammation function was studied by using the differential genes expression analysis, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analyses (GSEA) and correlation analysis. RESULTS:Most glycolysis-related genes had higher expression in breast cancer compared to normal tissue. Higher phosphoglycerate kinase 1 (PGK1) expression was associated with poor prognosis. High glycolysis group had upregulated immune/inflammation-related genes expression, upregulated immune/inflammation pathways especially IL-17 signaling pathway, higher enrichment of multiple immune/inflammation cells such as Th2 cells and macrophages. However, high glycolysis group was associated with lower infiltration of tumor-killing immune cells such as NKT cells and higher immune checkpoints expression such as PD-L1, CTLA4, FOXP3 and IDO1. CONCLUSIONS:In conclusion, the enhanced glycolysis activity of breast cancer was associated with pro-tumor immunity. The interaction between tumor glycolysis and immune/inflammation function may be mediated through IL-17 signaling pathway.

SUBMITTER: Li W

PROVIDER: S-EPMC7029444 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Comprehensive analysis of the association between tumor glycolysis and immune/inflammation function in breast cancer.

Li Wenhui W Xu Ming M Li Yu Y Huang Ziwei Z Zhou Jun J Zhao Qiuyang Q Le Kehao K Dong Fang F Wan Cheng C Yi Pengfei P

Journal of translational medicine 20200218 1

<h4>Background</h4>Metabolic reprogramming, immune evasion and tumor-promoting inflammation are three hallmarks of cancer that provide new perspectives for understanding the biology of cancer. We aimed to figure out the relationship of tumor glycolysis and immune/inflammation function in the context of breast cancer, which is significant for deeper understanding of the biology, treatment and prognosis of breast cancer.<h4>Methods</h4>Using mRNA transcriptome data, tumor-infiltrating lymphocytes ...[more]

PMID: 32070368

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Project description:PurposeProstate cancer is the most common malignant urinary tumor among men. Treatments are currently unsatisfactory for advanced prostate cancer. Cancer biology remains the basis for developing new antitumor drugs. Therefore, it is crucial to study the metabolic reprogramming, immune microenvironment, and immune evasion of tumors. This study aimed to clarify the relationship between tumor glycolysis and immune function in prostate cancer.Materials and methodsWe downloaded the gene expression matrix and clinical data of prostate cancer from The Cancer Genome Atlas. We studied the expression profiles and prognostic significance of glycolysis-related genes and used CIBERSORT to identify the proportion of tumor-infiltrating immune cells. Through differential gene expression analysis, gene ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis, and correlation analysis, we further explored the relationship between glycolytic activity and immune function. We also performed immunohistochemistry, Western blot and RT-qPCR experiments using human prostate cancer tissue and cell lines to verify the expression of some glycolytic genes, macrophage infiltration and polarization.ResultsAmong glycolysis-related genes, the expression of SLC16A3 in prostate cancer tissues was lower than that in normal tissues, but its high expression was associated with poor prognosis. In the high SLC16A3 expression group, several glycolysis-related genes also showed high expression, which was confirmed by immunohistochemistry experiments and Western blot. In high-glycolysis group, the expression of immune-related genes and the interleukin-17 (IL-17) signaling pathway were upregulated. CD8+ T cells, regulatory T cells, macrophages, and other immune cells were highly enriched. Among them, M2 macrophage infiltration was associated with poor prognosis.ConclusionThe enhanced glycolytic activity of prostate cancer may contribute to the formation of a pro-tumor immune microenvironment. The IL-17 signaling pathway may play an important mediating role in the interaction between tumor glycolysis and immune function.

Project description:ImportanceWhy some triple-negative breast cancers (TNBCs) have high and others have low immune cell infiltration is unknown. Understanding how immune surveillance shapes the cancer genome could help in the selection of patients and the development of more effective immunotherapy strategies.ObjectiveTo examine the association between genomic metrics and the extent of immune infiltration in TNBCs.Design, setting, and participantsThis study, performed from June 1, 2015, through January 31, 2017, used DNA and RNA sequencing data and messenger RNA expression results from The Cancer Genome Atlas (TCGA) breast cancer data set (n = 1215) to calculate previously described immune metagene expression values and histologic lymphocyte counts to quantify immune infiltration and assign prognostic categories to TNBCs. It used the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set as an independent validation cohort. The study compared clonal heterogeneity, somatic total mutational load, neoantigen load, and somatic copy number alteration levels between immune-rich TNBC cohorts with good prognosis and immune-poor TNBC cohorts with poor prognosis. The study also compared the distribution of mutations in 119 canonical cancer genes.Main outcomes and measuresCorrelation between immune prognostic category and genomic metrics of the cancer.ResultsThis study of 193 TNBC samples with patient survival information found an inverse association between clonal heterogeneity and immune metagene expression (? = ?0.395, P = 2 ×?10?8). The study also found an inverse association between immune metagene expression and somatic copy number alteration levels (? = ?0.484, P = 2 ×?10?10). Lymphocyte-rich TNBCs with good prognosis had significantly lower mutation and neoantigen counts than did lymphocyte-poor TNBCs with poor prognosis. The robustness of the study results was confirmed by using various immune metagenes in the same TCGA data set and in the independent METABRIC data set.Conclusions and relevanceThis study suggests that immune-rich TNBCs may be under an immune surveillance that continuously eliminates many immunogenic clones, resulting in lower clonal heterogeneity. These cancers may also represent the subset of TNBCs that could derive benefit from immune checkpoint inhibitor therapy to tilt the balance in favor of the immune system.

Project description:BackgroundPrior studies showed that tumor glycolysis and tumor immune evasion are interdependent. However, a systematic investigation of the association between tumor glycolysis and tumor immunity in various cancers remains lacking.MethodsUsing the Cancer Genome Atlas (TCGA) datasets, we explored the association between glycolytic activity and immune signatures in 14 cancer types. We also explored the associations between glycolytic activity and tumor immunity associated genetic features, including PD-L1 expression, tumor mutation burden (TMB), and tumor aneuploidy. Moreover, we performed in vitro experiments to verify some findings from bioinformatics analysis. Furthermore, we explored the association between tumor glycolytic activity and immunotherapy response.FindingsGlycolytic activity was likely correlated with active immune signatures in various cancers and highly glycolytic tumors presented an immune-stimulatory tumor microenvironment. Compared to TMB and aneuploidy, glycolytic activity was a stronger and more consistent predictor for immune signatures in diverse cancers. Both computational and experimental analyses showed that glycolysis could increase PD-L1 expression in tumor. Glycolytic activity had a strong correlation with apoptosis which was a strong positive predictor for immune signatures, suggesting that apoptosis could be an important medium connecting glycolytic activity with immune activity in cancer. Finally, highly glycolytic tumors exhibited a better immunotherapy response and a favorable survival in the immunotherapy setting.InterpretationTumor glycolysis may increase tumor immunity in diverse cancers. Glycolytic activity enhances PD-L1 expression on tumor cells and thus promotes anti-PD-1/PD-L1 immunotherapy response. Thus, the tumor glycolytic activity could be a predictive biomarker for immunotherapy response in diverse cancers. FUND: This work was supported by the China Pharmaceutical University (grant numbers 3150120001, 2632018YX01 to XW).

Dataset Information

Comprehensive analysis of the association between tumor glycolysis and immune/inflammation function in breast cancer.

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Comprehensive analysis of the association between tumor glycolysis and immune/inflammation function in breast cancer.

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