Unraveling triple-negative breast cancer tumor microenvironment heterogeneity: towards an optimized treatment approach
A partir de l'analyse de 1 512 échantillons tumoraux issus de différents sous-types moléculaires de cancer du sein triplement négatif, cette étude met en évidence un microenvironnement tumoral distinct pour chacun de ces sous-types moléculaires
Background : Recent efforts of gene expression profiling analyses recognized at least 4 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 was 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 (LAR) tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, LAR 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 chromosome 5q and 15q regions including genomic loss of MHC-related genes showed reduced cytotoxic activity, as a plausible immune escape mechanism.
Conclusion : 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.
Journal of the National Cancer Institute , article en libre accès, 2018