TSLP-Stimulated T Helper 2 Cells Induce Senescence in Advanced Breast Cancer

Abstract

Thymic Stromal Lymphopoietin, or TSLP, has a prominent role in inducing type II immune response, which is commonly associated with a tumor promotion. However, our studies have shown that TSLP induction is capable of driving T helper (Th) 2 polarization, which can block carcinogenesis by inducing terminal differentiation in a spontaneous breast and lung cancer models. Therefore, the TSLP induction can potentially be a viable strategy for cancer immunoprevention. In the impact of TSLP induction on advanced cancer with altered cellular phenotypes is unknown. Using an established MMTV-PyMTtg breast cancer cell line, we hereby show that TSLP-stimulated Th2 cells also possess an antitumor effect in advanced breast cancer. In contrast to early breast cancer suppression, the antitumor immunity mediated by TSLP-stimulated CD4+ T cells in advanced breast cancer consists of the induction of senescent-like phenotype in cancer cells. Inflammatory CD4+ T cells induce a senescent-like phenotype in breast cancer cells through the release of canonical Th1 cytokines, IFN-γ and TNF-α, which directly bind to their receptors on cancer cells. Our findings reveal a novel mechanism of TSLP-activated CD4+ T cells in immunity against advanced breast cancer, mediated by cellular senescence as a distinct effector mechanism for cancer immunotherapy.