Targeting the immune microenvironment to treat breast cancer.
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In tumor microenvironment, the crosstalk between infiltrating inflammatory cells and tumor cells creates a cytokine milieu which can promote both oncogenesis and tumor rejection. We have found an IL-13 dominant cytokine environment existing in breast cancer tissue, and the IL-13 is pathogenic since blocking IL-13 using a neutralizing antibody in vivo could prevent tumor growth. Furthermore, DCs are involved critically in breast tumor progression, very possibly through regulating Th1/Th2 polarization, since our previously in vivo data show that in the absence of DCs, CD4⁺ and CD8⁺ T cells fails to facilitate tumor growth in a xenograft model. Thus, it is important to unveil how DCs behave in the breast cancer microenvironment, and how DCs crosstalk with cancer cells or other stromal cells. In this study, we have shown that pro-tumor inflammation in breast cancer is driven by cancer cell-derived thymic stromal lymphopoietin (TSLP) that induces OX40L expression on dendritic cells (DCs). OX40L⁺ DCs generate inflammatory CD4⁺ T cells producing TNF-α and IL-13 (iTh2). Furthermore, we found high levels of IL-1β in breast cancer microenvironment of the patients. IL-1β level is positively correlated with the levels of IL-13 and TSLP. Importantly, IL-1β level is associated with the stage of the disease. IL-1β induces TSLP production from breast cancer cells lines in a dose- dependent manner in vitro. Cancer cells induce IL-1β both transcriptionally and translationally in mDCs and monocytes in a contact-dependent manner. This is mediated by cancer cell-derived TGF-β. Moreover, TGF-β -activating kinase 1 (TAK1) signaling is involved in caspase-1 activation and TGF-β-dependent IL-1β production. Blocking TGF-β in vivo prevents tumor growth through decrease IL-1β production. Administration of IL-1R antagonist anakinra prevents tumor growth in vivo, blocks OX40L expression on mDCs, and blocks iTh2 generation. Thus targeting the immune microenvironment through blockade of IL-1β represents a novel approach to treat breast cancer.