Single-cell transcriptomic profiling of immune landscape in triple-negative breast cancer during neoadjuvant chemotherapy.

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype, typically requiring neoadjuvant chemotherapy (NAC) as an obligatory component of the treatment regimen. Achieving a pathological complete response to NAC is associated with improved long-term outcomes for patients with TNBC. The functional status of the immune system plays a critical role in NAC efficacy. Herein, we presented the investigation of systemic and local immune landscape during the initial course of NAC treatment and identify factors that contribute to chemotherapy resistance of TNBC. Using single-cell RNA sequencing, we demonstrated that the transcriptional profile remained stable in a patient who responded to NAC, while a non-responder exhibited significant dysregulation in the expression of genes involved in stress response, apoptosis, immune cell proliferation, and differentiation within lymphocyte and monocyte populations. During the first course of NAC, circulating cytotoxic CD8 T cells in the non-responder patient overexpressed granzymes B and H, granulysin, and perforin. In contrast, expression of these factors decreased in CD8 T cells within the tumor. Finally, we identified for a first time a signature of myeloid-derived suppressor cells (MDSC) within the S100А^highMHC^low monocyte population and calculated an MDSC score for both the responder and the non-responder TNBC patients. An elevated MDSC score in the non-responder was validated using data from an independent cohort of patients with poor NAC response. Our data underscores the importance of immune system functionality in determining chemotherapy efficacy in TNBC.