2025/01/22 by Antoine Debiesse, Manuela Pereira Abrantes, Lyvia Moudombi +22 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Nursing · #Endoplasmic Reticulum Stress and Disease #Immune cells in cancer #Vitamin C and Antioxidants Research
paper · pdf · doi:10.1101/2025.01.17.633444
openalex publication_date 2025/01/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
ABSTRACT Breast cancer (BC) is the leading cause of cancer-related death in women. However, early detection of BC remains a major clinical challenge and represents a significant obstacle to effective prevention. To improve early clinical management, a deeper understanding of the preneoplastic immune microenvironment of BC is crucial. Among innate immune populations, neutrophils have emerged as important modulators of tumor development, but their role during the initiation of BC remains poorly understood. By integrating depletion experiments with transcriptomic profiling of sorted preneoplatic epithelial cells and neutrophils in spontaneous breast cancer mouse models, we observed that neutrophils contribute to tumor surveillance of preneoplastic stage with the activation of the unfolded protein response (UPR) in the preneoplastic epithelial compartment. To decipher the early anti-tumoral role of neutrophil, we developed an in vitro co-culture model of human mammary epithelial cells undergoing oncogenic stress with activation of the UPR (eHMEC), with human primary neutrophils. eHMEC display an immunoactive secretome as well as immunogenic membrane ligands, and neutrophils are the only immune cell population detecting eHMEC immunogenic signals leading to their recruitment, activation, production of reactive oxygen species and degranulation. Altogether, our work identifies for the first-time neutrophils as the earliest immune cell involved in immunosurveillance of preneoplastic BC epithelial cells, paving the way for potential therapeutic approaches targeting neutrophils to intercept early steps of BC tumorigenesis.