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 subtypes. Although T cells are the predominant TIL population, 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) cell differentiation and that these CD8 T cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8 T 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 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 cells will be crucial for successful immunotherapeutic development in BC.

Accumulation of CD103+ CD8+ T cells in a cutaneous melanoma micrometastasis

“…In the occult micrometastasis, we observed a prominent population of CD8 + CD103 + T cells in close proximity to SOX10 + melanoma cells, suggesting that human T RM cells can survey dormant melanoma cells and maintain immune equilibrium. This is in line with recent reports demonstrating the presence of CD103 + T RM in close proximity to tumor cells in patients with different types of cancers, including melanoma and breast cancer . Such results further echo our findings in mouse skin where T RM cells can directly interact with and control dormant melanoma microlesions .…”

“…Accordingly, the generation of large numbers of T RM cells in skin is associated with improved immune control and suppressed cancer progression. Several recent reports in a multitude of human cancers, including melanoma, suggest that T RM cells can promote immune surveillance and that their strong accumulation serves as a prognostic biomarker for improved clinical outcomes . However, those studies have focused on advanced and, most likely, immune‐escaped tumors.…”

“…The population of tumor‐associated lymphocytes in many advanced cancers contains CD8 + T cells that express transcriptional hallmarks of tissue‐resident memory T (T RM ) cells, including a lack of expression of the transcription factor, Kruppel‐like factor 2 and, consequently, an absence of tissue‐exit receptors such as S1PR1 and CCR7 . T RM cells are sessile cells that permanently reside within tissues without recirculating around the body .…”

Dissection of gastric cancer heterogeneity for precision oncology

“…Such qualitative differences of the immune cell infiltrate between patients hold the potential to serve as prognostic and predictive biomarkers in the context of IO drugs, and further unlock novel therapeutic IO targets. For instance, single‐cell analysis of BC T cells identified a specific tissue‐resident memory subset (T RM cells) that appeared to augment immunosurveillance, thereby introducing a potentially ideal target for IO modulation . Notably, single‐cell‐derived transcriptomic signatures of the T RM cell cluster were found to identify BC patients with significantly improved prognosis.…”

Resident Breast T Cells: The Troops Are Already There

“…Traditional methods such as flow cytometry and immunohistochemistry can only enumerate immune cell types using a limited number of established markers. In this study, Savas et al 4 applied single cell transcriptome sequencing to study triple-negative breast cancer (TNBC) tumor tissues and delineate the transcriptomic profiles of tumor-infiltrating T cells (TIL). This study clearly identified the presence of CD8 + TIL harboring features of tissue-resident memory T cells (T RM ) in TNBC and demonstrated superior prognostic value of a new CD8 + T RM gene signature over CD8 expression for predicting survival of TNBC patients.…”