Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity

Towards an Optimized Treatment Approach

Yacine Bareche; Laurence Buisseret; Tina Gruosso; Edwina Girard; David Venet; Floriane Dupont; Christine Desmedt; Denis Larsimont; Morag Park; Françoise Rothé; John Stagg; Christos Sotiriou


J Natl Cancer Inst. 2020;112(7):708-719. 

In This Article

Abstract and Introduction


Background: Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity.

Methods: Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided.

Results: We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism.

Conclusions: Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.


Triple-negative breast cancer (TNBC), representing 15%–20% of all breast cancers (BCs), has the worst outcome among BC subtypes and is known to be a heterogeneous disease at the clinical, biological, and genomic levels. Gene expression analyses have led to the identification of several molecular subtypes with distinct mutational profiles, genomic alterations, and biological processes, including basal-like (BL), immunomodulatory (IM), luminal androgen receptor (LAR), mesenchymal (M), and mesenchymal stem-like (MSL).[1–4] TNBC treatment remains challenging because therapeutic options are essentially limited to chemotherapy.[5]

Cancer development, progression, and treatment resistance are known to be influenced by genetic and epigenetic alterations as well as cross talk between tumor cells and their microenvironment. The tumor microenvironment (TME) is composed of multiple cell types, including fibroblasts, adipose and immune-inflammatory cells, and blood and lymphatic vascular networks.[6] TNBC subtype is associated with the highest tumor-infiltrating lymphocyte (TIL) levels. High TILs were associated with better clinical outcome and response to neoadjuvant chemotherapy.[7–9]

Several agents targeting TME immune components by inducing or enhancing antitumor immunity are under development.[10] Cancer immunotherapy immune checkpoint blockers (ICB) have changed the treatment paradigm in a variety of neoplastic diseases.[11] In BC, immunotherapy with ICB has demonstrated clinical activity and survival benefit, mostly in advanced TNBC and HER2+ subtype.[12–14] However, a benefit to ICB was observed in only a minority of BC patients, highlighting the need to better elucidate the mechanisms of treatment resistance allowing us to identify patients who will benefit the most from immunotherapy.