Immune gene signatures in triple-negative breast cancers characterized by varying levels of chromosomal instability.

Abstract

1096 Background: Triple-negative breast cancer (TNBC) is generally characterized by high levels of chromosomal instability (CIN) and an intense immune infiltration. However, the link between these two hallmarks and its implications for clinical practice has not been fully elucidated. Methods: We generated eight immune metagenes representing various immune components: natural killer [NK], dendritic cells [DC], T-cells [TC], B-cells [BC], cytotoxic T-cells [CT], interferon [IFN], nuclear factor-κB [NF-kB], and macrophages [M]. Publicly available gene expression data from forty-two data sets, including 862 TNBC samples, were collected. TNBC tumors were clustered in three main subgroups (Basal-Like [BL1/2], Immunomodulatory [IM], and Mesenchymal/Mesenchymal Stem-Like [MS]) using transcriptomic profiling. The CIN70 signature was used to stratify TNBC patients according to the levels of CIN. Statistical analyses were performed using Mann–Whitney U test and Kaplan-Meier analyses. Results: The majority of TNBC samples showed a high level of CIN (83%), and several immune modules were differentially expressed between CIN-high and CIN-low tumors. Specifically, CT, NK, DC, M, and NF-kB signatures were overexpressed in CIN-low TNBC ( p < 1.0E-04). We then evaluated the distribution of genomic instability among TNBC molecular subgroups. Noteworthy, the CIN-high group was composed by a comparable proportion of BL1/2 (39%) and MS (35%) tumors, while CIN-low TNBCs were consistently enriched for MS cancers (61%). Higher expression of the NK, M, and IFN metagenes lead to better survival in CIN-high tumors ( p = 1.9E-02, p = 2.1E-04, and p = 1.1E-03, respectively). Only IFN had the same correlation to survival in CIN-low ( p = 1.4E-02). Conclusions: TNBCs with low levels of CIN may principally enclose M/MSL tumors, which are characterized by an intense immune infiltration and overall good prognosis. Conversely, the TNBC CIN-high group is more heterogeneous in terms of both biological features and levels of immune infiltrates. Therapeutic strategies to promote and boost immune response in the genomically unstable TNBC subgroup warrant further investigation.