Parity and lactation induce T-cell-mediated breast cancer protection

Sep 30, 2026

Uploaded by Finn

Parity and breastfeeding reduce breast cancer risk, especially triple-negative disease, but the underlying immunological mechanisms have remained unclear. The study links parity with increased CD8+ T cells in human normal breast tissue, including cells with a tissue-resident-memory-like profile. In mouse models, pregnancy followed by lactation and involution accumulates CD8+ T cells in the mammary gland, suppressing tumour growth and enhancing intratumoural immune infiltration, dependent on CD8+ T cells. The effect requires a full lactation–involution cycle, and parous women’s primary TNBC shows greater T-cell infiltration and better clinical outcomes across preclinical models and over 1,000 patient samples.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages36

Reading Time1 h 31 min

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Article Summary

Parity and breastfeeding reduce breast cancer risk

Human evidence: CD8+ T-cell increases in normal breast tissue

Mouse models: lactation–involution drives CD8+ T-cell accumulation

Dependence on CD8+ T cells and requirement of full cycle

Clinical relevance in primary TNBC from parous women

Article | Parity and lactation induce T-cell-mediated breast cancer protection | | | | --- | --- | --- | | [https://doi.org/10.1038/s41586-025-09713-5](https://doi.org/10.1038/s41586-025-09713-5)
Received: 2 August 2024 Accepted: 6 October 2025 Published online: 20 October 2025 Open access
Check for updates | Balaji Virassamy1,2,52, Franco Caramia1,2,52, Peter Savas1,2,52, Michael A. Harris1,2,52, Jia-Wern Pan3, Jianan Wang1,2, Emmaline Brown1, Megan M. R. O’Malley1,2, Courtney T. van Geelen1,2, Michael Hun1,2, Thomas N. Burn4, Sneha Sant1, Jamieson D. Ballan1,2, Jasmine Kay1,2,
Luis E. Lara Gonzalez1,2, Kylie Clarke1, Han Xian AwYeang1,2, Rejhan Idrizi1,2, Metta Jana1,2, Damon J. Challice1, Roberto Salgado1,5, Heather Thorne1,2, kConFab consortium*,
Cathie Poliness6, Sophie Nightingale6, Soo-Hwang Teo3, Terence P. Speed7, Jane Visvader8,9, Paul J. Neeson1,2, Phillip K. Darcy1,2, Laura K. Mackay4 ✉ & Sherene Loi1,2 ✉
Parity and breastfeeding reduce the risk of breast cancer, particularly triple-negative breast cancer (TNBC)1,2, yet the immunological mechanisms underlying this protection remain unclear. Here we show that parity is associated with increased numbers of CD8+ T cells, including cells with atissue-resident-memory-like phenotype within human normal breast tissue. In mouse models, pregnancy followed by lactation and involution drove the accumulation of CD8+ T cells in the mammary gland, coinciding with reduced tumour growth and increased intratumoural immune cell infiltration, effects that were abrogated by CD8+ T cell depletion. Importantly, this CD8+ T-celldependent tumour control was observed only after a complete cycle of lactation and involution. Consistent with this, primary triple-negative breast cancers from parous women exhibited greater T cell infiltration and improved clinical outcomes. Together, these findings, spanning preclinical models andover 1,000 patient samples, provide insights into how reproductive history shapes breast immunity, positioning CD8+ T cells as key mediators of parity-associated protection and informing strategies for both the prevention and the treatment of breast cancer. | | | It is widely recognized that parity and lactation are associated with a | | anti-tumour responses and is associated with reduced breast cancer | | reduced long-term risk of breast cancer1,2. Parity is thought to protect by | | recurrence8,10,11. We also showed that TRM-like cells were present in both | | reshaping mammary epithelial cell differentiation and growth pathways | | breast tumoursand cancer-unaffected normal breast tissue, implicat- | | that occur during pregnancy, lactation and involution, thereby reducing | | ing them in treatment response and long-term immune surveillance | | susceptibility to malignant transformation overtime3–5. While parity | | of the breast. | | has been associated with a decreased risk of hormone-receptor-positive | | Post-partum, immune cell populations in mammary tissue undergo | | breast cancer, breastfeeding appears to confer amore specific reduc- | | considerable modulation: pregnancy and lactation are followed by | | tion in the risk of triple-negative breast cancer (TNBC)1,6. The cellular | | widespread apoptosis and tissue remodelling in the process known as | | and molecular mechanisms underlying this association are unclear. | | involution12,13. Changes in immune subsets, such as increased natural | | Deeper understanding could enable new subtype-specific prevention | | killer T (NKT) cells in the post-involution mammary gland, suggest | | and treatment strategies for breast cancer. This could be particularly | | a parity-induced immune surveillance mechanism14. Furthermore, | | relevant for women at higher risk ofTNBC, such as those who carry | | circulating T cells increases in parous women have been observed to | | germline pathogenic variants, or for groups with poorer outcomeseven | | persist for months post-partum andarethou

FAQs

How does parity relate to CD8+ T cells in normal breast tissue?

Parity is associated with increased numbers of CD8+ T cells, including cells with an tissue-resident-memory-like phenotype in human normal breast tissue.

What role do pregnancy, lactation, and involution play in mouse tumour outcomes?

In mouse models, pregnancy followed by lactation and involution drives CD8+ T-cell accumulation in the mammary gland, coinciding with reduced tumour growth and increased intratumoural immune infiltration.

Is CD8+ T-cell-mediated protection observed after any stage of reproductive changes?

No. CD8+ T-cell-dependent tumour control is observed only after a complete cycle of lactation and involution, and it is abolished by CD8+ T-cell depletion.

Sep 30, 2026

Uploaded by Finn