Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach

Abstract

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.

Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple‐negative breast cancer

“…Different prediction models have been developed for TNBC clinical outcomes and treatment sensitivity, especially regarding the tumor microenvironment and immune features 15,29 . In addition, intertumor and intratumoral heterogeneity predict not only clinical outcomes but also treatment sensitivity 30 . To date, several clinical trials have proven that PD‐L1 is a promising target for metastatic TNBC, whereas the effect of other immune checkpoint targets remains unclear in both early‐stage and metastatic TNBC 3,4,6 .…”

<p>Construction and Analysis of a Long Non-Coding RNA-Associated Competing Endogenous RNA Network Identified Potential Prognostic Biomarkers in Luminal Breast Cancer</p>

“…The current target-therapies are mostly concentrated on HER-2 overexpressed subtype, such as Trastuzumab and Pertuzumab, 2,3 while immunotherapies are aimed at triple-negative breast cancer (TNBC) due to its higher immunogenicity. 4,5 Quite a number of prognostic markets and targets were identified. [6][7][8] Unlike the two subtypes, patients with ER-or PR-positive BC, termed luminal subtype, are considered at a lower risk and endocrine therapy has achieved a considerable success.…”

Impact and Intricacies of Bone Marrow Microenvironment in B-cell Lymphomas: From Biology to Therapy

“…Lymphoma cells co-injected with MSCs have shown evidence of decreased apoptosis, indicating that there may be an immunosuppressive component resulting from lymphoma cell-stromal cell interaction [88]. Enhanced recruitment of MSCs has been found to be facilitated by the chemokine CXC-chemokine ligand 12 (CXCL12) produced by tumor cells within the BM microenvironment [90]. A large number of CD14+ HLA-DR monocytic MDSCs, frequently found along with tumor cells has also been correlated with poor prognosis in DLBCL [91].…”