Classification of triple-negative breast cancers based on Immunogenomic profiling

Abstract

Background: Abundant evidence shows that triple-negative breast cancer (TNBC) is heterogeneous, and many efforts have been devoted to identifying TNBC subtypes on the basis of genomic profiling. However, few studies have explored the classification of TNBC specifically based on immune signatures that may facilitate the optimal stratification of TNBC patients responsive to immunotherapy. Methods: Using four publicly available TNBC genomics datasets, we classified TNBC on the basis of the immunogenomic profiling of 29 immune signatures. Unsupervised and supervised machine learning methods were used to perform the classification. Results: We identified three TNBC subtypes that we named Immunity High (Immunity-H), Immunity Medium (Immunity-M), and Immunity Low (Immunity-L) and demonstrated that this classification was reliable and predictable by analyzing multiple different datasets. Immunity-H was characterized by greater immune cell infiltration and anti-tumor immune activities, as well as better survival prognosis compared to the other subtypes. Besides the immune signatures, some cancer-associated pathways were hyperactivated in Immunity-H, including apoptosis, calcium signaling, MAPK signaling, PI3K-Akt signaling, and RAS signaling. In contrast, Immunity-L presented depressed immune signatures and increased activation of cell cycle, Hippo signaling, DNA replication, mismatch repair, cell adhesion molecule binding, spliceosome, adherens junction function, pyrimidine metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and RNA polymerase pathways. Furthermore, we identified a gene co-expression subnetwork centered around five transcription factor (TF) genes (CORO1A, STAT4, BCL11B, ZNF831, and EOMES) specifically significant in the Immunity-H subtype and a subnetwork centered around two TF genes (IRF8 and SPI1) characteristic of the Immunity-L subtype. Conclusions: The identification of TNBC subtypes based on immune signatures has potential clinical implications for TNBC treatment.