Pregnancy and breastfeeding leave behind long-lived CD8+ T lymphocytes that provide lasting immune protection in breast tissue, according to new research, a discovery that could reshape understanding of breast cancer (BC) prevention and treatment. The findings, described as a “paradigm shift” by researchers, were presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, held recently in Berlin, Germany, and published simultaneously in Nature.

CD8+ T-Cell Infiltration in Breast Tissue

It has long been recognized that women who have been pregnant and have breastfed have a lower risk for BC, particularly triple-negative BC (TNBC), which is one of the most aggressive subtypes. “But the exact reason is not known,” said Sherene Loi, BC oncologist at the Peter MacCallum Cancer Centre in Melbourne, Australia, during a press conference at ESMO 2025.

“For many years, we believed this protection was mainly due to hormonal changes and structural remodeling of breast tissue following pregnancy and lactation,” she explained.

Understanding the biological mechanisms behind this protective effect could open new possibilities for prevention and treatment — the central goal of Loi’s research team.

Using single-cell RNA sequencing, flow cytometry, and multiplex imaging, the investigators analyzed normal breast tissue from more than 250 women who had undergone breast reduction or prophylactic mastectomy. The cohort represented diverse backgrounds, including African, American, European, and Asian populations.

The analyses focused on CD8+ T-cell infiltration, their phenotypes, and how these immune patterns correlated with clinical outcomes.

Pregnancy’s Lasting Immune Legacy

The study found that normal breast tissue from women who had given birth contained significantly more CD8+ T lymphocytes, including long-lived tissue-resident memory cells, than tissue from women who had never been pregnant. These immune cells were shown to persist for decades after childbirth.

Parallel studies in mouse models supported these findings: A full cycle of pregnancy, breastfeeding, and involution (return of the breast to its pre-pregnancy state) enriched mammary CD8+ T cells, provided protection against TNBC tumor growth, and was associated with greater T-cell infiltration in tumors. These protective effects disappeared when CD8+ T cells were experimentally depleted.

In human data, women who had been pregnant and had breastfed showed greater intratumoral CD8+ T-cell density and better survival in early-stage TNBC than those who had not.

BC Immunity

The findings suggest that reproductive history has a lasting influence on immune surveillance in breast tissue through durable CD8+ T lymphocytes.

“These results change our understanding of immunity in breast cancer,” said Loi. “Immunity should be seen not only as a therapeutic target but also as a determinant of cancer risk. This paradigm shift highlights how immune reprogramming linked to reproductive history could become a new pathway for prevention and for optimizing immunotherapy in triple-negative breast cancer.”

Loi reported having relationships with Novartis, Bristol Myers Squibb, AstraZeneca/Daiichi Sankyo, Roche Genentech, MSD, Pfizer, Gilead Sciences, Nektar Therapeutics, Eli Lilly, and others. She declared receiving research funding from the National Breast Cancer Foundation Australia, National Health and Medical Research Council, Peter MacCallum Cancer Foundation, and Breast Cancer Research Foundation in New York. 

This story was translated from Medscape’s French edition.