Improving Immune Response in Ovarian Cancer by Modulating the Wnt Pathway
[Technical Report, Annual Report]
University of Alabama
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In ovarian cancer, upregulation of the Wntbeta-catenin pathway leads to chemoresistance, poor prognosis, and has been correlated to T-cell exclusion in the tumor microenvironment. Our objective was to investigate whether inhibiting the Wnt pathway in the tumor could reverse this, creating a more T-cell inflamed TME, and thus, decreasing tumor growth and improving survival in a syngeneic ovarian cancer model. Additionally, we investigated whether the absence of beta-catenin in antigen-presenting cells would decrease tumor growth. In order to clarify if improved tumor recognition with decreased Wnt signaling was dependent on CD8 T-cells, we treated our mouse models with anti-CD8beta antibody in combination with Wnt inhibition. We investigated the effects of inhibiting Porcupine with a small molecule inhibitor, CGX1321. Mice injected with ID8 or ID8p53-- cells were treated with CGX1321. Treatment decreased ID8 tumor burden and improved survival. Using Nanostring, showed that CGX1321 treatment leads to an increase in T-cell, macrophage, and dendritic cell functions. Macrophages and DCs increased in the TME with CGX1321 treatment. In mice that lacked beta-catenin in DCs, there was less tumor growth, showing that not only decreasing Wnt signaling in the tumor itself can cause decreased tumor growth, but also decreasing it in DCs has a similar effect. CGX1321treatment did not have the same effect on tumor burden when given with anti-CD8beta antibody, thus supporting that PORCN inhibition is partially dependent on CD8 T-cells.
- Medicine and Medical Research