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However, no studies have examined whether reproductive factors and hormone use modulate the immune microenvironment of breast tissue. We prospectively evaluated the associations of reproductive factors and exogenous hormone use with breast tumor and normal-adjacent tissue immune cell markers among 935 breast cancer cases in the Nurses\u2019 Health Studies. We deconvoluted immune cell abundance using CIBERSORTx and derived gene expression signatures of markers for immune checkpoint (PD1, PDL1, and CTLA4), co-regulatory signal and antigen presentation (MHC class I\/ II and T cell receptor), and mammary cytokine signaling. Linear regression was used adjusting for confounders. Patterns of associations between reproductive factors and immune profile differed between tumor and normal-adjacent tissues and by estrogen receptor (ER) status. Tumors from postmenopausal women had significantly higher pro-inflammatory cytokine signaling and antigen presentation compared with tumors from premenopausal women (FDR\u2005\u2264\u20050.05). Several reproductive factors were nominally associated with immune profiles of normal-adjacent tissues. For example, parous women had higher CD8 T cell infiltration, higher PDL1 expression, and lower cytokine signaling (P\u2005\u2264\u2005.05); women who ever breastfed showed higher infiltration of NK cells and T helper cells in normal-adjacent tissue of ER+\u2005tumors but lower infiltration of CD8 T cell and monocyte, and higher expression of cytokine signaling in normal-adjacent tissue of ER\u2212 tumors (P\u2005\u2264\u2005.05). Our study demonstrates for the first time in a large epidemiologic study that reproductive factors may influence breast tumor immune microenvironment and sheds light on potential immune regulation for breast cancer prevention.<\/jats:p>","DOI":"10.1093\/carcin\/bgaf028","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T02:38:48Z","timestamp":1748572728000},"source":"Crossref","is-referenced-by-count":2,"title":["The impact of reproductive factors on breast tumor and normal-adjacent tissue immune profile from menarche to menopause"],"prefix":"10.1093","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0220-5128","authenticated-orcid":false,"given":"Cheng","family":"Peng","sequence":"first","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2484-151X","authenticated-orcid":false,"given":"Yuxi","family":"Liu","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115 ,","place":["United States"]},{"name":"Department of Epidemiology , Harvard T.H. Chan School of Public Health , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujing J","family":"Heng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Bodelon","sequence":"additional","affiliation":[{"name":"Department of Population Science, American Cancer Society , Atlanta, GA 30303 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Stover","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center , Columbus, OH 43210 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy Y","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle D","family":"Holmes","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A Heather","family":"Eliassen","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA 02115 ,","place":["United States"]},{"name":"Department of Epidemiology , Harvard T.H. Chan School of Public Health , Boston, MA 02115 ,","place":["United States"]},{"name":"Department of Nutrition , Harvard T.H. Chan School of Public Health , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-8103","authenticated-orcid":false,"given":"Peter","family":"Kraft","sequence":"additional","affiliation":[{"name":"Department of Epidemiology , Harvard T.H. Chan School of Public Health , Boston, MA 02115 ,","place":["United States"]},{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute , Rockville, MD 20850 ,","place":["United States"]},{"name":"Department of Biostatistics , Harvard T.H. Chan School of Public Health , Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rulla M","family":"Tamimi","sequence":"additional","affiliation":[{"name":"Department of Epidemiology , Harvard T.H. Chan School of Public Health , Boston, MA 02115 ,","place":["United States"]},{"name":"Department of Population Health Sciences, Weill Cornell Medicine , New York, NY 10025 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"2025071007222023600_CIT0001","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, adaptive, and acquired resistance to cancer immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"2025071007222023600_CIT0002","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1126\/science.aaf2834","article-title":"CANCER IMMUNOLOGY. 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