期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 65, 期 10, 页码 1159-1167出版社
SPRINGER
DOI: 10.1007/s00262-016-1879-5
关键词
Cancer; Dendritic cell-based immunotherapy; HIF-1 alpha; Hypoxia
Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1 alpha, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1 alpha inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-gamma, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1 alpha inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine.
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