Parity and lactation induce T-cell-mediated breast cancer protection.

Abstract

Parity and breastfeeding reduce the risk of breast cancer, particularly triple-negative breast cancer (TNBC), yet the immunological mechanisms underlying this protection remain unclear. Here we show that parity is associated with increased numbers of CD8T cells, including cells with a tissue-resident-memory-like phenotype within human normal breast tissue. In mouse models, pregnancy followed by lactation and involution drove the accumulation of CD8T cells in the mammary gland, coinciding with reduced tumour growth and increased intratumoural immune cell infiltration, effects that were abrogated by CD8T cell depletion. Importantly, this CD8 T-cell-dependent tumour control was observed only after a complete cycle of lactation and involution. Consistent with this, primary triple-negative breast cancers from parous women exhibited greater T cell infiltration and improved clinical outcomes. Together, these findings, spanning preclinical models and over 1,000 patient samples, provide insights into how reproductive history shapes breast immunity, positioning CD8T cells as key mediators of parity-associated protection and informing strategies for both the prevention and the treatment of breast cancer.