CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation
Margherita Boieri, Anna Malishkevich, Ranya Guennoun, Emanuela Marchese, Sanne Kroon, Kathryn E. Trerice, Mary E. Awad, Jong Ho Park, Sowmya Iyer, Johannes Kreuzer, Wilhelm Haas, Miguel N. Rivera, Shadmehr Demehri
Abstract
Cancer immunology research is largely focused on the role of cytotoxic immune responses against advanced cancers. Herein, we demonstrate that CD4+ T helper (Th2) cells directly block spontaneous breast carcinogenesis by inducing the terminal differentiation of the cancer cells. Th2 cell immunity, stimulated by thymic stromal lymphopoietin, caused the epigenetic reprogramming of the tumor cells, activating mammary gland differentiation and suppressing epithelial-mesenchymal transition. Th2 polarization was required for this tumor antigen-specific immunity, which persisted in the absence of CD8+ T and B cells. Th2 cells directly blocked breast carcinogenesis by secreting IL-3, IL-5, and GM-CSF, which signaled to their common receptor expressed on breast tumor cells. Importantly, Th2 cell immunity permanently reverted high-grade breast tumors into low-grade, fibrocystic-like structures. Our findings reveal a critical role for CD4+ Th2 cells in immunity against breast cancer, which is mediated by terminal differentiation as a distinct effector mechanism for cancer immunoprevention and therapy.