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

Tess O'Meara; Michal Marczyk; Tao Qing; Vesal Yaghoobi; Kim Blenman; Kimberly Cole; Vasiliki Pelekanou; David L Rimm; Lajos Pusztai

doi:10.1200/PO.19.00350

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

JCO Precis Oncol. 2020 Jun 26:4:PO.19.00350. doi: 10.1200/PO.19.00350. eCollection 2020.

Authors

Tess O'Meara¹, Michal Marczyk^{1

2}, Tao Qing¹, Vesal Yaghoobi³, Kim Blenman¹, Kimberly Cole³, Vasiliki Pelekanou^{3

4}, David L Rimm³, Lajos Pusztai¹

Affiliations

¹ Department of Medical Oncology, Yale School of Medicine, New Haven, CT.
² Data Mining Division, Silesian University of Technology, Gliwice, Poland.
³ Department of Pathology, Yale School of Medicine, New Haven, CT.
⁴ Sanofi, Oncology and Translational Medicine, Bridgewater Township, NJ.

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 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.