肿瘤源IL-35趋化单核细胞促胰腺癌血管新生的分子机制研究

Pancreatic cancer is one of the most incurable malignant tumors. Small improvement has been made during the past three decades. VEGF-targeted anti-angiogenic therapy has made progress in multiple tumors except pancreatic cancer. Thus, we need to elucidate the mechanism of angiogenesis in pancreatic cancer and select the proper subpopulations for anti-angiogenic therapy. In our recent study published in Nature Communications (Corresponding Authors), we discovered that pancreatic cancer cells secreted immune-regulatory factor, IL-35, which is associated with multiple non-immune-regulatory functions, such as the invasion and metastasis of pancreatic cancer, indicating that tumor-derived IL-35 exerts a wide and complicated effect. Previous clinical analysis suggested that IL-35 was correlated with micro-vascular density in pancreatic cancer, and in vitro experiments excluded direct angiogenesis promotion by IL-35. Further investigation indicated that IL-35 promoted angiogenesis via monocyte/macrophage. This study aims to explore the function and mechanism of pancreatic cancer to recruit monocyte/macrophage and regulate the secretion of pro-angiogenic factors, via clinical-pathological data, in vitro functional and transcription-regulatory analysis, SCID mice and PDX (patient-derived xenograft models). Furthermore, we will complete the pre-clinical safety and efficacy evaluation, and provide rationale for the therapy targeting IL-35 and selection of the benefited subpopulation for anti-angiogenic therapy.

胰腺癌是最难治的恶性肿瘤之一，近30年临床治疗进展缓慢。以VEGF为靶点的抗血管新生治疗在多种肿瘤取得疗效，然而在胰腺癌疗效欠佳。因此，我们急需解析胰腺癌的血管新生机制，明确治疗的靶点和优势人群。我们近期在Nat Commun（通讯作者）中发表文章， 发现胰腺癌细胞分泌免疫调节因子IL-35，并且参与胰腺癌的侵袭、转移等非免疫调节行为，提示肿瘤源IL-35功能广泛、复杂。前期临床病理发现IL-35与胰腺癌微血管密度相关，然而体外证据排除IL-35的直接促血管作用。 进一步研究提示IL-35促胰腺癌血管新生可能通过单核巨噬细胞介导。 本课题拟通过临床病理学分析、体外功能评价及转录调控研究、体内SCID鼠移植瘤和PDX 模型研究揭示胰腺癌招募单核细胞并调控其分泌促血管新生因子的分子机制，进而完善临床前安全性及有效性评价，为靶向IL-35治疗及抗血管新生优势人群的筛选提供理论基础。

胰腺癌是恶性程度极高的消化系统肿瘤之一，对于多种治疗耐药，使得目前整体临床治疗效果徘徊不前，虽然近年来预后稍有改善，但是五年生存率仍然不足10%。目前临床抗肿瘤血管新生治疗药物集中于靶向VEGF/VEGFR通路，但对于胰腺癌的治疗效果不佳。因此，我们需要我们从新的角度审视胰腺癌的血管新生机制，更新现有的治疗策略。白介素35（IL-35）是近年发现的调节T细胞分泌的强免疫抑制分子，本课题通过临床组织样本、内体外新生血管实验明确IL-35在胰腺癌组织中的异常表达与组织血管密度及单核巨噬细胞的浸润相关。体外实验证实了胰腺癌细胞来源的IL-35通过单核巨噬细胞促进胰腺癌血管新生；进一步通过共培养探索肿瘤源性IL-35招募单核巨噬细胞浸润的分子机制，发现IL-35以CCL5依赖性方式募集单核细胞分泌CXCL1和CXCL8，促进胰腺癌的血管新生。进一步体内实验通过选择性阻断IL-35并联合吉西他滨(胰腺癌一线化疗药)可明显提高抗肿瘤效果。此项研究揭示了IL-35参与胰腺肿瘤参与血管新生病生理行为的分子机制，这为揭示胰腺癌血管新生机制提供了新思路，为靶向IL-35治疗及抗血管新生优势人群的筛选提供理论基础。