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<p>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<sub>RM</sub>-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<sub>RM</sub>-like cells. Single-cell transcriptomics revealed the expanded T<sub>RM</sub>-like cells were heterogeneous, comprising CD8αβ<sup>+</sup> and CD8αα<sup>+</sup> subsets. Lineage tracing showed that these T<sub>RM</sub>-like cells acquire effector functions and contribute to tumor control. Depletion of T<sub>RM</sub>-like cells abrogated breast tumor protection in parous mice, while enhanced IL-2Rβ signaling-induced T<sub>RM</sub>-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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Tabinda Hussain,
  • Melrine Pereira,
  • David Chisanga,
  • Caleb A. Dawson,
  • Adelynn Tang,
  • Pathum Thilakasiri,
  • Jayendra Singh,
  • Meagan Ruppert,
  • Ashleigh Davey,
  • Kevin Man,
  • Patrizia Murer,
  • Liam Neil,
  • Conor McGuinness,
  • Yuxi Cao,
  • Chun-Hsi Su,
  • Rebecca Nightingale,
  • Katie Gdak,
  • Genevieve Mason,
  • Damien Grinsell,
  • Hamish Farrow,
  • Natalie Ngan,
  • Stephanie Liong,
  • Jian Wu,
  • Sarah McLucas,
  • Pepper Schedin,
  • Arttu Junnila,
  • Matti Poutanen,
  • Nicole M. Haynes,
  • Nicholas D. Huntington,
  • Michael Chopin,
  • Thomas Gebhardt,
  • Bhupinder Pal,
  • Daniel T. Utzschneider,
  • John M. Mariadason,
  • Axel Kallies,
  • Kara L. Britt,
  • Ajithkumar Vasanthakumar

摘要

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 (TRM-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 TRM-like cells. Single-cell transcriptomics revealed the expanded TRM-like cells were heterogeneous, comprising CD8αβ+ and CD8αα+ subsets. Lineage tracing showed that these TRM-like cells acquire effector functions and contribute to tumor control. Depletion of TRM-like cells abrogated breast tumor protection in parous mice, while enhanced IL-2Rβ signaling-induced TRM-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.