DataSheet1_Hydroxytyrosol Inhibits MDSCs and Promotes M1 Macrophages in Mice With Orthotopic Pancreatic Tumor.docx

The poor immunotherapy of pancreatic cancer is mainly due to its complex immunosuppressive microenvironment. The Mediterranean diet contributes to low cancer incidence. Hydroxytyrosol (HT) derived from olive oil has multiple health-promoting effects, but its therapeutic effect on pancreatic cancer remains controversial. Here, we evaluated the inhibitory effect of HT on mouse pancreatic cancer, and the effect of HT on the immune microenvironment. We found that HT can inhibit the proliferation of Panc 02 cells through signal transducer and activator of transcription (STAT) 3/Cyclin D1 signaling pathway. In the tumor-bearing mice treated with HT, the orthotopic pancreatic tumors were suppressed, accompanied by a decrease in the proportion of myeloid-derived suppressor cells (MDSCs) and an increase in the proportion of M1 macrophages. In addition, we found that HT inhibited the expression of immunosuppressive molecules in bone marrow (BM)-derived MDSCs, as well as down-regulated CCAAT/enhancer-binding protein beta (C/EBPβ) and phosphorylation of STAT3. Moreover, HT enhanced the anti-tumor effect of anti-CD47 antibody in vivo. HT combined with plumbagin (PLB) induced more Panc 02 cells death than HT or PLB alone. This combination therapy not only inhibited the accumulation of MDSCs, but also promoted the infiltration of CD4+ and CD8+ T cells in the tumors. In summary, HT is a potential immunomodulatory drug for the treatment of pancreatic cancer.

胰腺癌的免疫治疗效果欠佳，其主要原因在于其复杂的免疫抑制微环境。地中海饮食（Mediterranean diet）可降低癌症发病风险。橄榄油来源的羟基酪醇（Hydroxytyrosol, HT）具有多种有益于机体健康的生物学效应，但其用于胰腺癌治疗的效果仍存在争议。本研究评估了HT对小鼠胰腺癌的抑瘤作用，以及HT对肿瘤免疫微环境的调控效应。研究结果显示，HT可通过信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3）/细胞周期蛋白D1（Cyclin D1）信号通路，抑制Panc 02细胞的增殖。在HT处理的荷瘤小鼠模型中，原位胰腺癌肿瘤的生长受到显著抑制，同时伴随髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）比例下降，以及M1型巨噬细胞比例升高。此外，本研究发现HT可抑制骨髓（bone marrow, BM）来源的MDSCs中免疫抑制分子的表达，同时下调CCAAT/增强子结合蛋白β（CCAAT/enhancer-binding protein beta, C/EBPβ）的表达水平，并抑制STAT3的磷酸化。进一步实验表明，HT可在体内增强抗CD47抗体的抗肿瘤活性。HT与白花丹素（plumbagin, PLB）联合使用时，相较于单独使用HT或PLB，可诱导更多Panc 02细胞发生死亡。该联合治疗策略不仅能够抑制MDSCs的肿瘤浸润与聚集，还可促进CD4+和CD8+ T细胞向肿瘤组织内的浸润。综上，HT是一种具有应用潜力的免疫调节类药物，可用于胰腺癌的治疗。