TSLP driven inflammation fosters breast tumor development (74.2)

Abstract

Abstract Solid tumors are often associated with aseptic inflammation. There are two types of inflammation that have opposing effects on tumors, chronic inflammation that promotes cancer survival and metastasis, and acute inflammation which triggers cancer destruction. Chronic inflammation is often linked with the presence of type 2-polarized macrophages induced by Th2 cytokines, IL-4 and IL-13. Our studies have demonstrated the presence in breast cancer tumors of inflammatory Th2 cells, which produce IL-13, IL-4, and TNF. These CD4+ T cells appear to play a key role in the disease as they accelerate breast tumor development in a xenograft model through the production of IL-13. Breast tumors appear to play a critical role in conditioning the infiltrating myeloid DCs (mDCs) to induce such inflammatory Th2 cells. Our recent results suggest that thymic stromal lymphopoetin (TSLP) plays a role in mDCs conditioning. Breast cancer cell lines and primary tumors from patients show TSLP protein expression. TSLP-neutralizing antibodies block the upregulation of OX40L by mDCs exposed to tumor supernatant and consequently block mDCs capacity to generate inflammatory Th2 cells in vitro. Targeting pattern recognition receptors on mDCs renders them resistant to TSLP signal. These mDCs don't phosphorylate STAT6, don't express OX40L and turn on the secretion of IL12p70. The final outcome is the block of inflammatory Th2 and tumor rejection. Thus, TSLP could serve as therapeutic target in breast cancer.