Browsing by Subject "Breast cancer."
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Item Reprogramming the immune environment in breast cancer via dendritic cells.(2013-09-24) Wu, Te-Chia.; Palucka, Karolina, 1959-; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.Breast cancer is the most common cancer among American women. The current therapies are not curative for some forms of breast cancer, especially breast cancers that do not express the growth factor and hormone receptors and metastatic cancers. Recently, immunotherapy become an anticipated option for breast cancer. Before approaching immunotherapy, it is important to firstly understand how is the immune microenvironment regulated in breast cancer to determine how it could be modulated for therapy. The human breast cancer microenvironment displays features of T helper 2 (Th2) immunity which promotes tumor development. Here we show that human breast cancer cells produce thymic stromal lymphopoietin (TSLP). Breast tumor supernatants, in a manner dependent on TSLP, induce expression of OX40L on dendritic cells (DCs). OX40L⁺ DCs are found in primary breast tumor infiltrates. OX40L⁺ DCs drive development of inflammatory Th2 cells producing interleukin 13 and tumor necrosis factor in vitro. Antibodies neutralizing TSLP or OX40L inhibit breast tumor growth and interleukin 13 production in a humanized mouse model of breast cancer. Thus, breast cancer cell-derived TSLP, by inducing OX40L expression on DCs, contributes to the Th2 immunity conducive to breast tumor development. In order to reprogram the inflammatory pro-tumor Th2 (iTh2) into anti-tumor Th1 microenvironment, we tested the impact of targeting the innate receptors on DCs to render the resistant to tumor environment. We show that intratumoral delivery of β-glucan, a natural ligand for dectin-1 expressed on DCs, blocks the generation of iTh2 cells leading to decreased IL-13 in the tumor microenvironment and prevents breast cancer development in vivo. β-glucan inhibits OX40L expression on tumor-associated DCs which is due to a block in STAT6 phosphorylation. β-glucan-treated DCs, when exposed to breast cancer supernatant, secrete higher levels of IL-12p70 and do not expand iTh2 cells thereby enabling the T helper 1 cells secreting IFN-γ. β-glucan exposed DCs expand CD8⁺ T cells that express CD103, a ligand for E-cadherin. These CD8+ T cells, which produce higher IFN-γ, Granzyme A and Granzyme B, accumulate in the tumors leading to enhanced tumor necrosis in vivo. DC reprogramming by β-glucan is dependent upon dectin-1 engagement. The ligand of TLR7/8 (CL075) and TLR3 (polyI:C) show the same effect in Th2 response inhibition but no effect on the functions of CD8 T cells. Taken together, our data demonstrate that exploiting pattern recognition receptors on tumor-infiltrating DCs enables cancer rejection.Item Targeting the immune microenvironment to treat breast cancer.(2014-06-11) Xu, Kangling.; Palucka, Karolina, 1959-; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.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.