Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, United States of America; Department of Gynecologic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, United States of America.
Gynecol Oncol. 2020 Jun;157(3):765-774. doi: 10.1016/j.ygyno.2020.03.010. Epub 2020 Mar 16.
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.
Wnt 通路突变是子宫内膜样和透明细胞上皮性卵巢癌（EOC）的标志。然而，没有 FDA 批准的针对 EOC 中 Wnt 通路的药物。Wnt 通路调节剂 Dickkopf 相关蛋白 1（DKK1）已成为有前途的治疗靶点。我们旨在研究 DKK1 的作用以及针对 DKK1 的单克隆抗体（DKN-01）在体内和卵巢癌小鼠模型中的作用。
我们研究了 DKK1 在 EOC 细胞系中的作用以及 DKK1 抑制的影响。然后，我们使用 ID8 同基因小鼠模型研究了 DKN-01 和 DKK1 过表达对肿瘤负担和抗肿瘤免疫细胞群的作用。
DKN-01 体外不会表型改变 ES2 细胞；然而，DKK1 抑制促进了 Wnt 信号。用 mDKN01 治疗 ID8 挑战的小鼠，肿瘤负担和免疫细胞群没有变化。过表达 DKK1 的 ID8 细胞挑战的小鼠的肿瘤负担与对照组相似（p=0.175）。然而，DKK1 的过表达减少了 CD45 白细胞浸润到腹膜（p=0.008）和大网膜（p=0.032），减少了自然杀伤（NK）和 CD8 T 细胞，并减少了活化的 CD8 T 细胞中干扰素-γ（IFNγ）的表达。
我们的结果表明，DKK1 抑制不会影响 ID8 卵巢癌模型中的肿瘤生长。DKK1 过表达改变了肿瘤微环境中的抗肿瘤免疫细胞群。因此，我们的发现证实了 DKK1 是 EOC 的一个新的治疗靶点，并表明 DKK1 抑制可能在联合免疫调节治疗中效果最佳。
