Novel approaches in cancer immunotherapy have led to effective therapeutics against late-stage cancers. However, the role of the immune system in protection against early-stage cancers remains uncertain. We have previously discovered that thymic stromal lymphopoietin (TSLP) blocks early stages of breast cancer development through activation of CD4+ T cells. TSLP is an epithelium-derived danger signal that plays a key role in initiating an immune response upon cell damage and stress. The aim of this study is to investigate the potential involvement of other epithelial-derived cytokines in the activation of an immune response against premalignant breast lesions. To identify these signals, we analyzed the expression of a wide range of epithelium-derived cytokines in normal mammary glands, premalignant lesions, and late-stage tumors of MMTV-PyMT (PyMTtg) and K14-Cre, Brca1f/f, p53f/f mouse models. These mice spontaneously develop breast tumors that resemble human luminal and basal-like breast cancers, respectively. Of the cytokines examined, IL-1a was highly expressed in premalignant lesions compared to mammary glands and tumors. Additionally, IL-12p40 was upregulated in both early and late stages of breast cancer compared to normal mammary gland. Other cytokines, like IL-7, IL-11, and IL-24, were highly expressed in the mammary gland, but their expression was lost during breast tumorigenesis. In conclusion, we identified upregulation of IL-1a and IL-12p40 in early-stage breast cancer, suggesting a role for these cytokines in inducing antitumor immunity in the breast. Furthermore, we demonstrate selection against expression of IL-7, IL-11, and IL-24 during the process of cancer initiation and promotion, suggesting a role in normal mammary gland homeostasis and possibly immunity against breast carcinogenesis. Taken together, we have identified potential novel therapeutic targets that can be leveraged for breast cancer immunoprevention.

Citation Format: Sanne Kroon, Kaitlin Dempsey, Margherita Boieri, Shawn Demehri. Epithelium-derived cytokines in breast carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B102.