Work

1170 Spatial transcriptomics identifies immune heterogeneity in estrogen receptor positive postpartum breast cancer

Year: 2026

Type: conference-abstract

Abstract: Background Postpartum breast cancer (PPBC) is an aggressive subtype of breast cancer (BC) diagnosed following childbirth and is associated with poor outcomes compared with age and stage matched nulliparous or parous BC. 1–3 Experimental models have demonstrated that postpartum mammary gland involution promotes extracellular matrix remodeling, immune suppression, and tumor progression.4–5 However, the immune landscape of young PPBC remains poorly characterized. We hypothesized that the tumor microenvironment (TME) of young estrogen receptor-positive (ER+) PPBC exhibits distinct spatially organized immune states that contribute to disease aggressiveness. To address this, we performed high-resolution spatial transcriptomic profiling of young PPBC tumors stratified by time since last childbirth.Methods Twenty ER + BC samples from women ≤45 years of age were included. Based on time since last childbirth (LCB), patients were categorized as PPBC1 (LCB ≤5 years), PPBC2 (LCB 6–10 years), and PPBC3 (LCB >10 years). Tissue microarrays were profiled using Visium HD spatial transcriptomics. Following sequencing and quality control, data were analyzed using standard spatial transcriptomic workflows. Differential gene expression (DGE), pathway enrichment, cell type annotation, and ligand-receptor interaction analyses were performed to characterize spatial differences in the TME across postpartum groups.Results Spatial clustering and DGE analyses identified both shared and group specific transcriptional programs across the three cohorts. Relative to PPBC2 tumors, PPBC1 tumors showed enrichment of inflammatory and tumor progression pathways. Compared with PPBC3 tumors, PPBC1 tumors exhibited enhanced metabolic pathways, but reduced immune and inflammatory signaling. Cell type annotation identified enrichment for immunosuppressive immune populations, including CD25 + CCR4+ regulatory T cells, exhausted T cells and macrophages in PPBC1 tumors. PPBC2 tumors were enriched for dendritic cell subsets, CD4+ and CD8+ effector memory T cells, and memory B cells, suggestive of a more immune-reactive microenvironment. PPBC3 tumors were characterized by enrichment of fibroblast and stromal cell populations. Ligand-receptor analysis demonstrated prominent extracellular matrix and adhesion-related signaling in PPBC1 tumors, including FN1-CD44/SDC4 and COL1A2-CD44/SDC4 interactions. PPBC2 tumors showed enrichment of VEGFA-VEGFR1/VEGFR2 signaling, whereas PPBC3 tumors were characterized by LAMA2-CD44 and COL6A1/COL4A2-SDC4 interactions.Conclusions ER + PPBC exhibit distinct, time-dependent immune microenvironments. Early postpartum tumors are characterized by enrichment of immunosuppressive cell populations, including regulatory and exhausted T cells, together with extracellular matrix-mediated signaling, whereas later postpartum tumors display a more immune-active phenotype. These findings highlight potential immune and stromal mechanisms driving PPBC aggressiveness and may inform the development of targeted therapeutic strategies.Acknowledgements 1. This work was supported by the Indian Council of Medical Research (ICMR) Intermediate Grant [ICMR Project ID: IIRPIG-2024-01-00934] awarded to Dr. Jyothi S. Prabhu. 2. The fellowship support to Vidya Nimbalkar by the Fogarty International Center of the National Institutes of Health under Award Number D43TW012274 (INSIGHT). 3. We gratefully acknowledge Nadathur Holdings and Bagaria Education Trust for their support of breast cancer research at the Division of Molecular Medicine, St. John’s Research Institute, India.References Amant F, Lefrère H, Borges VF, Cardonick E, Lambertini M, Loibl S, et al. The definition of pregnancy-associated breast cancer is outdated and should no longer be used. Lancet Oncol. 2021;22(6):753.Zhang Z, Bassale S, Jindal S, Fraser A, Guinto E, Anderson W, et al. Young-Onset Breast Cancer Outcomes by Time since Recent Childbirth in Utah. JAMA Netw Open. 2022;5(10):E2236763Goddard ET, Bassale S, Schedin T, Jindal S, Johnston J, Cabral E, et al. Association between postpartum breast cancer diagnosis and metastasis and the clinical features underlying risk. JAMA Netw Open. 2019;2(1):186997.Lefrère H, Lenaerts L, Borges VF, Schedin P, Neven P, Amant F. Postpartum breast cancer: Mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31(3):412–22.Basree MM, Shinde N, Koivisto C, Cuitino M, Kladney R, Zhang J, et al. Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer. Breast Cancer Res. 2019;21(1):80.Ethics Approval The study was approved by the Institutional Ethics Committee (IEC) of St. John’s Medical College (SJMC) (IEC Study Ref. No. 256/2024).

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1170