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 Padj = .009; METABRIC Padj = 4.09E-15), CD8+ T cells (TCGA Padj = .015; METABRIC Padj = 0.390), and M2-like macrophages (TCGA Padj= 4.68E-05; METABRIC Padj = .435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA Padj = 0.015; METABRIC Padj = .004) and M1-like macrophages (TCGA Padj = 9.39E-08; METABRIC Padj = 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 β (TGF-β) 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-β 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-β pathway and M2-like macrophages are promising strategies in immune-rich ER-positive BCs to augment antitumor immunity.

Mechanisms of Macrophage Plasticity in the Tumor Environment: Manipulating Activation State to Improve Outcomes

“…However, instead of promoting the re-growth of tissue resident cells, these factors drive tumor growth. Likewise, macrophages also secrete key effectors of vascularization, like the vascular endothelial growth factor (VEGF) (42,43), plateletderived growth factor (PDGF) (44) and transforming growth factor b (TGFb) (45) to promote angiogenesis (Figure 1). These physiologic processes are hijacked to increase blood flow to the tumor, increasing tumor cell access to oxygen and nutrients for continued cell proliferation.…”

“…These physiologic processes are hijacked to increase blood flow to the tumor, increasing tumor cell access to oxygen and nutrients for continued cell proliferation. M2 macrophages may also maintain tumor growth through the remodeling of the extracellular matrix (ECM) through secretion of matrix metalloproteases (MMPs) and other factors (45,46) (Figure 1).…”

The Immunology of Hormone Receptor Positive Breast Cancer

“…In general, NK cells account for a small portion of infiltrating lymphocytes in breast tumors ( 102 , 103 ). Interestingly, analyses of TCGA and METABRIC samples revealed HR+ tumors have lower NK cell gene expression compared to TNBC tumors and immune-rich HR+ tumors have a lower proportions of NK cells compared to immune-rich TNBC tumors ( 104 , 105 ). The combination of MHC-I downregulation and NK cell exclusion has not been analyzed in the literature and is an active line of investigation in our lab.…”

Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression

“…In this light, luminal BC still remains an orphan with regard to immunotherapy options. It is becoming clearer that the heterogeneity of the various BC subtypes (luminal vs. HER2+ vs. TNBC) possibly explains the marked diversity of the spontaneous immune-related mechanisms that are generated, making it likely that their manipulation through ICB or other strategies (i.e., vaccines) will vary depending on the subtype [21,22].…”