胰臟癌是具侵略性及複雜的發炎網絡所調控的癌症。介白素二十 (IL-20) 參與在許多類型癌症中，像是乳癌、前列腺癌、口腔癌。然而介白素二十是否參與在胰臟癌的發病機制中是未知的。介白素20是介白素10家族中的成員之一，介白素10家族中包含介白素10 (IL-10)、介白素20 (IL-20)、介白素22 (IL-22)、介白素24 (IL-24) 及介白素26 (IL-26)。IL-20會透過兩組接受介白素20的接受器，其中一組接受器由介白素20接受器第一型 (IL-20 receptor-1; IL-20R1)與介白素20接受器第二型 (IL-20 receptor 2; IL-20R2) 組合而成。另一組由介白素20接受器第二型與介白素22接受器第一型 (IL-22 receptor 1; IL-22R1) 組合而成。IL-20R1/IL-20R2 組合成的接受器可以同時接受IL-19、IL-20與IL-24訊號。另一組由IL-20R2/IL-22R1組合成的接受器可同時接受IL-20與IL-24訊號。IL-20 在發炎中扮演重要角色，因此我們認為IL-20可能在癌症中執行促腫瘤發展，預期IL-20可能在癌症進展中對腫瘤發展是有利的因素。我們假設 IL-20 可能在胰臟癌病理機制中扮演下多重角色:
(1). IL-20 水平升高有助於腫瘤增生及對腫瘤微環境發展。
(2). IL-20 的分泌會促進其他發炎因子相繼誘導出來。
(3). IL-20 與癌症相關的巨噬細胞分化及浸潤相關。
(4). IL-20可能直接參與胰臟組織的纖維化。
(5). IL-20 可能參與與腫瘤免疫檢查站 PD-L1的調控。
(6). IL-20 可能參與免疫 T 細胞的 PD-1調控。
(7). 抗介白素20抗體與抗PD-1拮抗劑的複合式治療可能提供更好抑癌效果。
(8). 抗介白素20抗體可能有助於減緩癌症惡病質病徵
從我們的初步數據顯示，IL-20在胰臟癌病患和胰臟癌動物模型的腫瘤細胞上有高度的表達，因此我們推測 IL-20 可能參與胰臟癌的發病機制，並且我們也評估抗介白素20單株抗體在胰臟癌動物模型上的治療效果。從動物實驗數據表明，抗介白素20單株抗體大大延長自發性罹患胰臟腫瘤基因小鼠 (KPC mice) 及後天原位移植胰臟腫瘤小鼠 (orthotopic PDAC model) 的整體壽命。不僅如此，介白素20單株抗體有抑制腫瘤生長及降低免疫檢查站 PD-L1 表達。我們利用基因敲除技術將鼠源胰臟癌細胞的介白素 20 接受器一型 ( IL-20 R1) 抑制其表現，進一步證明也可以減緩腫瘤發展。另外抗介白素20抗體有效減緩在胰臟癌動物模型中癌症惡病質的病狀。除了介白素20抗體在癌細胞有抑制的效果外，介白素20抗體對腫瘤微環境有效減少腫瘤相關巨噬細胞的浸潤及增加活化態的免疫毒殺T細胞數量。因此本研究對於IL-20在胰臟癌的病理機制進一步釐清並且証明利用介白素20抗體在臨床治療胰臟癌將有很大潛能及貢獻。

Pancreatic cancer is an aggressively malignant cancer with complicated crosstalk between proinflammatory cytokines and cancer cells. Interleukin 20 (IL-20) is a proinflammatory cytokine involved in some types of cancer, such as breast cancer, prostate cancer, and oral cancer. However, little is known about its role in pancreatic cancer. IL-20 is a member of the IL-10 family, which includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26. IL-20 signals through two heterodimeric receptors: IL-20R1/IL-20R2 or IL-22R1/IL-20R2. IL-20R1/IL-20R2 heterodimer is also shared by IL-19 and IL-24, while IL-22R1/IL-20R2 is only shared by IL-24.
IL-20 plays a pleiotropic role in inflammation. Thus, IL-20 was considered as a tumor mediator. It was hypothesized that IL-20 could be a favorable factor for cancer progression. Our preliminary data demonstrated that IL-20 was highly expressed on tumor cells of pancreatic cancer samples from patients and animal models with pancreatic cancer. Hence, we proposed that IL-20 may be involved in the pathogenesis of pancreatic cancer. We hypothesized that IL-20 was involved in the progression of pancreatic cancer through the following eight mechanisms:
(1). IL-20 might be elevated and supported tumor cell proliferation in the tumor microenvironment.
(2). IL-20 might induce the production of proinflammatory cytokines and further promoted macrophage infiltrating into the pancreas.
(3). IL-20 might have an effect on macrophage polarization and tumor infiltration.
(4). IL-20 may also be involved in the tissue fibrosis of the pancreas. Thus, IL-20 may be involved in the multiple steps of cancer progression.
(5). IL-20 may be involved with PD-L1 regulation in pancreatic cancer.
(6). IL-20 may affect PD-1 expression of T cells in PDAC.
(7). Combined therapy with anti-IL-20 mAb and anti-PD-1 antibodies may have better efficacy for inhibiting tumor progression.
(8). Targeting IL-20 might alleviate the symptoms of cancer-induced cachexia
Higher IL-20 expression in pancreatic ductal adenocarcinoma (PDAC) was correlated with poor overall survival. We evaluated the therapeutic benefit of 7E in genetically engineered LSL-KrasG12D/+, Trp53flox/flox, and Pdx1-Cre (KPC) mouse model, and an orthotopic model of PDAC. 7E treatment not only prolonged survival, alleviated pancreatic fibrosis, and downregulated PD-L1 expression in both murine models but also inhibited tumor growth and symptoms of cancer-induced cachexia in the orthotopic model of PDAC. In addition, deficiency of IL-20R1 (interleukin-20 receptor 1) in murine PDAC cells suppressed pancreatic tumor growth. In addition to IL-20 impact on tumor, IL-20 induced M2-like macrophage polarization and attenuated PD-1 expression in cytotoxic T cells. Of note, combined therapy with an IL-20 antagonist and an anti-PD-1 antibody significantly enhanced antitumor activity in the orthotopic PDAC model.
Therefore, IL-20 plays a critical role in tumor progression in PDAC. We believe that our research will elucidate the role of IL-20 in pancreatic cancer and its clinical implication, and the antagonist of IL-20 might be a novel therapeutics for treating PDAC.

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