Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

Abstract

The quantity of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival, particularly in triple-negative and HER2-overexpressing BC subtypes¹. Although T cells are the predominant TIL population², the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6,311 T cells isolated from human BCs and show that significant heterogeneity exists in the infiltrating T cell population. We demonstrate that BCs with a high number of TILs contained CD8⁺ T cells with features of tissue-resident memory T (T_RM) cell differentiation and that these CD8⁺ T_RM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8⁺ T_RM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple-negative breast cancer (TNBC) and provided better prognostication than CD8 expression alone. Our data suggest that CD8⁺ T_RM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of T_RM cells will be crucial for successful immunotherapeutic development in BC.