Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer

• Published in: Gynecologic oncology 2020-06, Vol.157 (3), p.765-774
• Main Authors: Betella, Ilaria, Turbitt, William J., Szul, Tomasz, Wu, Binghao, Martinez, Alba, Katre, Ashwini, Wall, Jaclyn A., Norian, Lyse, Birrer, Michael J., Arend, Rebecca
• Format: Article
• Language: English
• Subjects: B-catenin; DKK1; Immunotherapy; Ovarian cancer; Wnt
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2020.03.010

Wnt pathway mutations are a hallmark of endometrioid and clear cell subtypes of epithelial ovarian carcinoma (EOC). However, no drugs targeting the Wnt pathway in EOC are FDA-approved. Dickkopf-related protein 1 (DKK1), a modulator of the Wnt pathway, has emerged as a promising therapeutic target. We aimed to examine the role of DKK1 and the effects of a monoclonal antibody against DKK1 (DKN-01) in vivo and in a murine model of ovarian cancer. We examined in vitro the role of DKK1 and the effects of DKK1 inhibition in EOC cell lines. We then studied in vivo the role of DKN-01 and DKK1 overexpression on tumor burden and anti-tumor immune cell populations using the ID8 syngeneic mouse model. DKN-01 did not phenotypically alter ES2 cells in vitro; however, DKK1 inhibition promoted Wnt signaling. Tumor burden and immune populations were unchanged in ID8 challenged mice treated with mDKN01. Mice challenged with ID8 cells overexpressing DKK1 had tumor burden similar to controls (p = 0.175). However, the overexpression of DKK1 decreased CD45+ leukocyte infiltration into the peritoneum (p = 0.008) and omentum (p = 0.032), reducing both natural killer (NK) and CD8 T cells, and reducing interferon-gamma (IFNγ) expression on activated CD8 T cells. Our results suggest that DKK1 inhibition does not affect tumor growth in the ID8 ovarian cancer model. DKK1 overexpression alters anti-tumor immune populations within the tumor microenvironment. Thus, our findings confirm DKK1 as a new therapeutic target in EOC and suggest that DKK1 inhibition may function best in a combinatorial, immune-modulatory therapy. •Increase in Wnt/β-catenin pathway activity correlates with a “cold” tumor and low levels of tumor infiltrating T cells.•DKK1 is increased with upregulation of the Wnt pathway and likely contributes to the lack of effective T cells in the TME.•In gynecologic cancers, elevated levels of DKK1 are associated with a more advanced clinical stage and a poorer prognosis.•Targeting DKK1 could potentially induce a “hot” TME and be used as a mechanism to improve the effects of immunotherapy.