Abstract 4948: T helper 2 cells block breast cancer promotion

Abstract

New immune-based strategies for cancer treatment including the activation of tumor-infiltrating CD8 + cytotoxic T lymphocytes (CTLs) have led to effective therapeutics against late-stage disease. However, the function of the immune system in combating the early-stage cancers remains uncertain. To establish a mechanism that activates immune cells against early carcinogenesis, we have studied the role of an epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), in early stages of breast cancer development. We have previously discovered that TSLP blocks breast carcinogenesis through the activation of CD4 + T cells that heavily infiltrate the sites of developing cancer in the breast gland without affecting the normal tissue.To investigate the mechanism by which TSLP-stimulated CD4 + T cells suppress spontaneous breast cancer development, we used MMTV-PyMT transgenic mouse models (PyMT tg ) that spontaneously develop breast tumors and resemble the human luminal breast cancer. These mice were crossed into TSLP transgenic mice that produce TSLP under the promoter of a skin-specific keratin 14 promoter (K14-TSLP tg ), plus additional knockouts including TSLPR-/- and IL4r α ;-/-. Tumor development was arrested in K14-TSLP tg ;PyMT tg mice compared to PyMT tg counterparts as their tumors failed to progress to high grade. The tumor suppressive mechanism of CD4 + T cells was mediated by a block in cancer cell proliferation, but not by cytotoxicity. Polarization of CD4 + T cells into T helper 2 (Th2) subtype was essential for blocking breast tumor development, and the tumor suppression was achieved by CD4 + T cells in the absence of CD8 + T and B cells. Finally, we found the basal levels of TSLP released by premalignant breast epithelial cells to be protective against the early phases of breast cancer development.In conclusion, we demonstrate that CD4 + Th2 cells block early stages of breast carcinogenesis. TSLP stimulated CD4 + Th2 cells induce an arrest in cancer cell proliferation, which represents a novel mode of immunity with great potential for the prevention and treatment of breast cancer. Citation Format: Margherita Boieri, Anna Malishkevich, Lauren Steidl, Kenneth Ngo, Sowmya Iyer, Mary Awad, Johannes Kreuzer, Wilhelm Haas, Miguel Rivera, Shadmehr Demehri. T helper 2 cells block breast cancer promotion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4948.