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)^1,2, yet the immunological mechanisms underlying this protection remain unclear. Here we show that parity is associated with increased numbers of CD8⁺ T 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 CD8⁺ T cells in the mammary gland, coinciding with reduced tumour growth and increased intratumoural immune cell infiltration, effects that were abrogated by CD8⁺ T 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 CD8⁺ T cells as key mediators of parity-associated protection and informing strategies for both the prevention and the treatment of breast cancer.