Wound healing‐like immune program facilitates postpartum mammary gland involution and tumor progression

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Abstract
Women diagnosed with breast cancer within 5 years postpartum have poor survival rates. The process of postpartum mammary gland involution, whereby the lactating gland remodels to its prepregnant state, promotes breast cancer progression in xenograft models. Macrophage influx occurs during mammary gland involution, implicating immune modulation in the promotion of postpartum breast cancer. Herein, we characterize the postpartum murine mammary gland and find an orchestrated influx of immune cells similar to that which occurs during wound healing. Further, the normal involuting gland may be in an immunosuppressed state as discerned by the transient presence of Foxp3+ regulatory T cells and IL‐10+ macrophages with T cell suppressive function. To determine the influence of the postpartum immune microenvironment on mammary tumor promotion, we developed an immune‐competent model. In this model, mammary tumors in the involution group are sixfold larger than nulliparous group tumors, have decreased CD4+ and CD8+ T cell infiltrates and contain a greater number of macrophages with the ability to inhibit T cell activation. Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL‐10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of αIL‐10 treatment. Relevance to women is implicated, as we find postlactational human breast tissue has transient high IL‐10+ and Foxp3+ immune cell infiltrate. These data show an immune modulated microenvironment within the normal involuting mammary gland suggestive of immunosuppression, that when targeted reduces tumor promotion, revealing possible immune‐based strategies for postpartum breast cancer.
Funding Information
  • Colorado's NIH/NCI Tissue Biobanking and Processing, and Flow Cytometry Shared Resource Cancer Center (P30CA046934)
  • NIH/NCATS Colorado CTSI (UL1 TR001082)
  • University of Colorado Safeway Gift Fund
  • Department of Defense Breast Cancer Research Program (to P.S. and V.B.) (#BC101904)
  • Grohne Family Foundation Award
  • NIH/National Cancer Institute (to P.S. and V.B.) (1R01CA169175)
  • Department of Defense Breast Cancer Research Predoctoral Grant (to H.M.) (#BC100910)

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