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

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 = .009; METABRIC = 4.09E-15), CD8 T cells (TCGA = .015; METABRIC = 0.390), and M2-like macrophages (TCGA = 4.68E-05; METABRIC = .435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA = 0.015; METABRIC = .004) and M1-like macrophages (TCGA = 9.39E-08; METABRIC = 6.24E-11) were higher in immune-rich TNBCs. Ninety-one immune-related genes (eg, , , , , ) 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, , , , ) 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 (, granzyme-B, perforin) and positively with M2-like macrophages (, , and and regulatory T-cell () 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.