Immunological Differences Between Immune-Rich Estrogen Receptor-Positive and Immune-Rich Triple-Negative Breast Cancers.
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- Record sourced from PubMed, PMID 32923897.
- Also identified by DOI 10.1200/PO.19.00350 and PMC identifier 7446500.
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Abstract
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. 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. Relative fractions of resting mast cells (TCGA <i>P</i> <sub>adj</sub> = .009; METABRIC <i>P</i> <sub>adj</sub> = 4.09E-15), CD8<sup>+</sup> T cells (TCGA <i>P</i> <sub>adj</sub> = .015; METABRIC <i>P</i> <sub>adj</sub> = 0.390), and M2-like macrophages (TCGA <i>P</i> <sub>adj</sub>= 4.68E-05; METABRIC <i>P</i> <sub>adj</sub> = .435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA <i>P</i> <sub>adj</sub> = 0.015; METABRIC <i>P</i> <sub>adj</sub> = .004) and M1-like macrophages (TCGA <i>P</i> <sub>adj</sub> = 9.39E-08; METABRIC <i>P</i> <sub>adj</sub> = 6.24E-11) were higher in immune-rich TNBCs. Ninety-one immune-related genes (eg, <i>CXCL14</i>, <i>CSF3R</i>, <i>TGF-B3</i>, <i>LRRC32/GARP</i>, <i>TGFB-R2</i>) and a transforming growth factor β (TGF-β) response metagene were significantly overexpressed in immune-rich ER-positive BCs, whereas 41 immune-related genes (eg, <i>IFNG</i>, <i>PD-L1</i>, <i>CTLA4</i>, <i>MAGEA4</i>) were overexpressed in immune-rich TNBCs in both discovery and validation data sets. TGF-β pathway member genes correlated negatively with expression of immune activation markers (<i>IFNG</i>, granzyme-B, perforin) and positively with M2-like macrophages (<i>IL4</i>, <i>IL10</i>, and <i>MMP9)</i> and regulatory T-cell (<i>FOXP3</i>) markers in both subtypes. Different immunotherapy strategies may be optimal in immune-rich ER-positive BC and TNBC. Drugs targeting the TGF-β pathway and M2-like macrophages are promising strategies in immune-rich ER-positive BCs to augment antitumor immunity.