Premalignancy induced B cell-centered immune aggregates for immune-prevention against triple negative breast cancer

Abstract Immune surveillance is believed to be a critical mechanism to eradicate premalignant mutant cells to prevent cancer. However, the cellular organization and mechanisms for immune surveillance remain largely unknown because premalignant mutant cells are “invisible” in patient samples and conventional animal models. To gain a glimpse into this process, our lab developed a genetically engineered mouse model recapitulating human basal-like breast cancer through unequivocal labeling of premalignant p53-Brca1 mutant cells with GFP. Using this model, we discovered prominent immune aggregates in close proximity to mutant ducts, which eventually disperse at the tumor stage. These immune aggregates manifest tertiary lymphoid structure (TLS)-like organization, enriched with activated B cells co-clustered with T cells and CD11b+ myeloid-derived cells. To fully characterize these TLS-like aggregates, we are profiling the dynamic changes in immune composition and activation status from premalignancy to malignancy. In parallel, to investigate the molecular mechanism behind their organization, we are studying the relevant chemokines, like CXCL13, and corresponding source cells. Ultimately, we plan to perform functional experiments to determine if these TLS-like structures are responsible for controlling the malignant progression of breast cancer. Our work provides direct evidence of how immune response against premalignant cells before breast cancer forms. Supported by grants from NIH (R01CA256199-01A1)