Pregnancy-induced tissue-resident memory-like T cells contribute to tumor control in breast cancer

Women who have full-term pregnancies have a reduced risk of breast cancer, although the underlying mechanisms are not well understood. Here we show that tissue-resident memory-like T (T_RM-like) cells are enriched in the breasts of parous women and mice compared to nulliparous individuals. These cells develop during mid-gestation, persist after lactation and are closely associated with mammary epithelial cells, suggesting dependence on epithelial-derived signals. Impaired alveolar differentiation or a deficiency in epithelial cell-derived cytokines interleukin (IL)-15 and transforming growth factor (TGF)β diminished the expansion of mammary T_RM-like cells. Single-cell transcriptomics revealed the expanded T_RM-like cells were heterogeneous, comprising CD8αβ⁺ and CD8αα⁺ subsets. Lineage tracing showed that these T_RM-like cells acquire effector functions and contribute to tumor control. Depletion of T_RM-like cells abrogated breast tumor protection in parous mice, while enhanced IL-2Rβ signaling-induced T_RM-like cells and conferred protection in nulliparous mice. Together, we show a mechanism by which pregnancy can induce anticipatory breast cancer protection in a tissue-specific manner.