Abstract IA17: TSLP-driven inflammation fosters development of epithelial tumors

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 cell survival, and metastasis, and acute inflammation which triggers cancer cell destruction. Chronic inflammation is often linked with the presence of type 2-polarized macrophages (M2), which are induced by Th2 cytokines, IL-4 and IL-13. Our recent 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 most recent results suggest that thymic stromal lymphopoetin (TSLP) secreted by cancer cells 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. The TSLP production is mediated by PAR2-signaling in cancer cells. PAR2 is expressed by all 4 breast cancer cell lines, and TSLP production can be induced upon PAR2-agonist peptide treatment. Similar observations were made by us and others in pancreatic cancer as well as lung cancer. Thus, TSLP could serve as therapeutic target in tumors of epithelial origin.