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.