Identification of Breast Cancer LCK Proto-Oncogene as a Master Regulator of TNBC Neutrophil Enrichment and Polarization

Abstract

The role of neutrophils in breast cancer shows that the N1 proinflammatory subtype can suppress and attack the tumor. In contrast, the N2 pro-tumor subtype aids the tumor in its survival, progression, and metastasis. Recently, more focus has been directed to the role of innate myeloid cells, specifically neutrophils, in regulating the responses of lymphoid populations both in the progression of cancer and in response to therapy. However, the exact crosstalk between breast cancer cells and neutrophils is poorly understood. In this work, we used in-silico assays to investigate the role of the bidirectional effect of neutrophils on metastatic TNBC. Our reanalysis of publicly available data reveals that most TNBC’s classified within the CE2 subtype are leukocyte-poor and have four major cell types in their ecotypes: dendritic cells, macrophages, fibroblasts, and epithelial cells. Further immune deconvolution of these patients revealed that a few cells significantly differed between groups, including macrophages, neutrophils, and T cells. All BC showed lower infiltrating neutrophils compared to healthy surrounding tissue. Treated TNBCs improved the count of infiltrating neutrophils in TNBC. Most TNBC patients have a unique CE2 ecotype, characterized by more basal-like epithelial cells, more neutrophils, and fewer mononuclear lymphocytes (B cells, macrophages M1, T cell CD4+ (non-regulatory), and T cell CD8+ and T regs). This can be related to our finding that CE2 TNBCs are characterized by a lower LCK and higher ERBB2, and their top DEGs are related to leukocyte activation and NFKB pathway.