Dataset Information

Immunological Differences Between Immune-Rich Estrogen Receptor-Positive and Immune-Rich Triple-Negative Breast Cancers.

ABSTRACT: PURPOSE:A subset of estrogen receptor-positive (ER-positive) breast cancer (BC) contains high levels of tumor-infiltrating lymphocytes (TILs), similar to triple-negative BC (TNBC). The majority of immuno-oncology trials target TNBCs because of the greater proportion of TIL-rich TNBCs. The extent to which the immune microenvironments of immune-rich ER-positive BC and TNBC differ is unknown. PATIENTS AND METHODS:RNA sequencing data from The Cancer Genome Atlas (TCGA; n = 697 ER-positive BCs; n = 191 TNBCs) were used for discovery; microarray expression data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n = 1,186 ER-positive BCs; n = 297 TNBCs) was used for validation. Patients in the top 25th percentile of a previously published total TIL metagene score distribution were considered immune rich. We compared expression of immune cell markers, immune function metagenes, and immuno-oncology therapeutic targets among immune-rich subtypes. RESULTS:Relative fractions of resting mast cells (TCGA P adj = .009; METABRIC P adj = 4.09E-15), CD8+ T cells (TCGA P adj = .015; METABRIC P adj = 0.390), and M2-like macrophages (TCGA P adj= 4.68E-05; METABRIC P adj = .435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA P adj = 0.015; METABRIC P adj = .004) and M1-like macrophages (TCGA P adj = 9.39E-08; METABRIC P adj = 6.24E-11) were higher in immune-rich TNBCs. Ninety-one immune-related genes (eg, CXCL14, CSF3R, TGF-B3, LRRC32/GARP, TGFB-R2) and a transforming growth factor ? (TGF-?) response metagene were significantly overexpressed in immune-rich ER-positive BCs, whereas 41 immune-related genes (eg, IFNG, PD-L1, CTLA4, MAGEA4) were overexpressed in immune-rich TNBCs in both discovery and validation data sets. TGF-? pathway member genes correlated negatively with expression of immune activation markers (IFNG, granzyme-B, perforin) and positively with M2-like macrophages (IL4, IL10, and MMP9) and regulatory T-cell (FOXP3) markers in both subtypes. CONCLUSION:Different immunotherapy strategies may be optimal in immune-rich ER-positive BC and TNBC. Drugs targeting the TGF-? pathway and M2-like macrophages are promising strategies in immune-rich ER-positive BCs to augment antitumor immunity.

SUBMITTER: O'Meara T

PROVIDER: S-EPMC7446500 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Immunological Differences Between Immune-Rich Estrogen Receptor-Positive and Immune-Rich Triple-Negative Breast Cancers.

O'Meara Tess T Marczyk Michal M Qing Tao T Yaghoobi Vesal V Blenman Kim K Cole Kimberly K Pelekanou Vasiliki V Rimm David L DL Pusztai Lajos L

JCO precision oncology 20200626

<h4>Purpose</h4>A subset of estrogen receptor-positive (ER-positive) breast cancer (BC) contains high levels of tumor-infiltrating lymphocytes (TILs), similar to triple-negative BC (TNBC). The majority of immuno-oncology trials target TNBCs because of the greater proportion of TIL-rich TNBCs. The extent to which the immune microenvironments of immune-rich ER-positive BC and TNBC differ is unknown.<h4>Patients and methods</h4>RNA sequencing data from The Cancer Genome Atlas (TCGA; n = 697 ER-posi ...[more]

PMID: 32923897

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Project description:BackgroundDirectly comparing gene expression profiles of estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers cannot determine whether differentially expressed genes between these two subtypes result from dysregulated expression in ER+ cancer or ER- cancer versus normal controls, and thus would miss critical information for elucidating the transcriptomic difference between the two subtypes.Principal findingsUsing microarray datasets from TCGA, we classified the genes dysregulated in both ER+ and ER- cancers versus normal controls into two classes: (i) genes dysregulated in the same direction but to a different extent, and (ii) genes dysregulated to opposite directions, and then validated the two classes in RNA-sequencing datasets of independent cohorts. We showed that the genes dysregulated to a larger extent in ER+ cancers than in ER- cancers enriched in glycerophospholipid and polysaccharide metabolic processes, while the genes dysregulated to a larger extent in ER- cancers than in ER+ cancers enriched in cell proliferation. Phosphorylase kinase and enzymes of glycosylphosphatidylinositol (GPI) anchor biosynthesis were upregulated to a larger extent in ER+ cancers than in ER- cancers, whereas glycogen synthase and phospholipase A2 were downregulated to a larger extent in ER+ cancers than in ER- cancers. We also found that the genes oppositely dysregulated in the two subtypes significantly enriched with known cancer genes and tended to closely collaborate with the cancer genes. Furthermore, we showed the possibility that these oppositely dysregulated genes could contribute to carcinogenesis of ER+ and ER- cancers through rewiring different subpathways.ConclusionsGPI-anchor biosynthesis and glycogenolysis were elevated and hydrolysis of phospholipids was depleted to a larger extent in ER+ cancers than in ER- cancers. Our findings indicate that the genes oppositely dysregulated in the two subtypes are potential cancer genes which could contribute to carcinogenesis of both ER+ and ER- cancers through rewiring different subpathways.

Dataset Information

Immunological Differences Between Immune-Rich Estrogen Receptor-Positive and Immune-Rich Triple-Negative Breast Cancers.

Publications

Immunological Differences Between Immune-Rich Estrogen Receptor-Positive and Immune-Rich Triple-Negative Breast Cancers.

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