Type 2 cytokines in breast epithelial homeostasis.

Abstract

e12588 Background: The widespread use of type 2 cytokine blockades (e.g., Dupilumab) has transformed treatment of inflammatory disorders, yet their impact on non-immune tissues, specifically the breast microenvironment, is unknown. This gap is notable as our prior work identified a novel, protective role of T helper 2 (Th2) immunity when induced in early breast cancer, challenging the traditional paradigm that Th2 cells are pro-tumorigenic. Interleukin-4 (IL-4) and IL-13 signal through common (IL-4Rα/IL-13Rα1) and unique receptors differentially expressed on lymphocytes and epithelial cells, and their therapeutic blockade may inadvertently affect antitumor responses. As breast cancer is the most common malignancy in women and is tightly regulated by CD4+ T cell-derived cytokines, characterizing the relative contributions of IL-4/13 to breast epithelial integrity is critical in ensuring the safety of Th2-targeted therapies. Methods: Immunofluorescence (IF) staining for IL-4Rα, CD117, and EpCAM was performed on normal female human breast glands and adjacent-to-tumor tissue across three age cohorts: ( < 30, 31-50, > 50 years). Human mammary organoids were treated with IL-4/13 to assess effects on epithelial differentiation using HALO image analysis. In vivo, IL-4Rα or IL-13 was removed from MMTV-PyMT spontaneous mammary tumor mice (Luminal B) and monitored for tumor kinetics, histopathology, and metastatic burden. Results: Quantitative IF analysis revealed an age-dependent decline in IL-4Rα expression, which was highest in young breast tissue. This loss was most prominent in the EpCAM+ luminal lineage, with significant decreases observed in both total luminal and CD117+ progenitor cells (p < 0.0001). Expression levels in both populations showed strong negative correlations with age (Total: r = -0.7085; Progenitor: r = -0.6612). Furthermore, IL-4/13 treatment at Day 7 decreased relative organoid count versus controls (p < 0.05). In murine models, global loss of either IL-4Rα receptor or IL-13 cytokine significantly accelerated breast tumor onset, increased tumor counts, reduced survival, and increased lung metastatic foci. Conclusions: Our findings establish IL-4/13 signaling axis as a critical regulator of mammary epithelial homeostasis that is diminished during aging and oncogenesis. Systemic IL-4Rα inhibition may impair antitumor responses, supporting the need for long-term clinical monitoring of breast tissue homeostasis in patients receiving Th2-targeted therapies.