CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation

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.

Thymic stromal lymphopoietin-stimulated CD4+ T cells induce senescence in advanced breast cancer

“…Our findings demonstrate a role for TSLP induction in the treatment of advanced breast cancer. These data complement our previous observation that TSLP induction mounts a robust Th2 cell response preventing breast tumor development by inducing terminal differentiation of the early-stage breast cancer cells ( Demehri et al, 2016 ; Boieri et al, 2022 ). Other studies have also shown that the Th2 cells can provide an antitumor effect during tumorigenesis ( Nishimura et al, 1999 ; Mattes et al, 2003 ; Lorvik et al, 2016 ).…”

“…Tslp tg mice that received primary tumor had delayed tumor growth and smaller tumors at endpoint compared with WT mice ( p < 0.0001, Figure 1A ). Transfer of primary tumors into Tslp tg mice led to development of low-grade fibrocystic-like tumors compared with high-grade tumors in WT mice ( Figure 1B ) ( Boieri et al, 2022 ). Tslp tg mice receiving PyMt cell line also showed significantly delayed tumor growth and smaller tumors compared with WT mice ( p < 0.0001, Figure 1C ).…”

“…Thus, a novel antitumor mechanism driven by TSLP-stimulated CD4 + T cells and delivered by TNF-α and IFN-γ cytokines results in the senescence of advanced breast cancer cells. Collectively, our research on TSLP induction in breast cancer reveals that during the early stages of breast cancer development, cancer cells respond to TSLP-activated CD4 + T cell immunity by undergoing terminal differentiation ( Boieri et al, 2022 ). In contrast, advanced cancer cells are no longer capable of initiating a differentiation program and they respond to TSLP-activated CD4 + T cell immunity by undergoing senescence.…”

“…Additionally, in response to TSLP, tumor cells have been shown to be secreting IL-1α that act on myeloid cells in the TME, which subsequently secrete TSLP back to tumor cells, creating an IL-1α/TSLP positive feedback loop ( Olkhanud et al, 2011 ; Pedroza-Gonzalez et al, 2011 ; Kuan and Ziegler, 2018 ). On the other hand, TSLP induction is capable of driving inflammatory Th2 cell activation, which blocks carcinogenesis by inducing terminal differentiation in a spontaneous breast and lung cancer models ( Demehri et al, 2016 ; Boieri et al, 2022 ; Guennoun et al, 2022 ). In addition, Th2 cell immunity plays a critical role in regulating tumor development, and depletion of Transforming Growth Factor (TGF)-β receptors on CD4 + T cells, but not CD8 + T cells, which can halt tumor progression in breast cancer ( Liu et al, 2020 ).…”

“…We have previously shown that K14-Tslp +/tg , MMTV-PyMt +/tg (Tslp tg , PyMt tg ) mice are protected against early breast cancer development ( Demehri et al, 2016 ; Boieri et al, 2022 ). However, it is unclear whether TSLP induction can also block tumor growth in advanced, metastatic breast cancer models.…”