Post-lactational involution promotes recruitment of local CD8+ T cells with a resident-phenotype that controls breast cancer growth

The mechanisms by which parity and breastfeeding mediate protection against breast cancer, particularly triple-negative breast cancer (TNBC), remain unclear. CD8+ T cells with a tissue-resident-like phenotype (TRM) are present in TNBCs and are associated with better clinical outcomes. In preclinical models of TNBC, CD8+ TRM-like cells can protect against BC recurrences. These cells are also present in healthy, non-cancer-affected breast tissue. We hypothesized that post-lactational involution could facilitate increased CD8+ T cell recruitment locally to the breast, improving immune surveillance against BC. Consistent with this, we observed significantly higher quantities of immune cells and CD103+CD8+ T cells in healthy breast tissue collected from parous vs. nulliparous women. In preclinical murine models, we observed that after a period of lactation and involution, CD8+ TRM-like cells increase in quantity the mammary gland. Using syngeneic models of TNBC, we show that these higher quantities of local CD8+ T cells in the mammary gland are associated with significantly decreased tumor growth, with higher intratumoral T cell content. We further find that parous women vs. nulliparous women who develop primary TNBC have significantly higher T cell infiltration in their tumors. Our data provide evidence that lactation and post-lactational involution result in quantitative and qualitative differences in local resident CD8+ T cells that can restrain mammary tumor outgrowth. Overall design: Single cell suspensions of parous normal breast tissue were obtained by enzymatic dissociation as previously described on the day of surgery. Viable cells were FACS sorted by propidium iodide staining for CD45+CD3+CD45RO+CCR7- sub-population that were and further sorted CD8+CD69+CD103+ and CD8+CD69+CD103- T cell subsets