载脂蛋白A-I模拟肽L-4F调控MDSCs的分子机制及其在胰腺癌中的作用

Pancreatic cancer is an aggressive malignancy and unresponsive to conventional radiation and chemotherapies. Therefore, the development of novel therapeutic strategies is urgently needed. The effect of Myeloid-derived suppressor cells (MDSCs) in mediating tumor immune escape, promoting tumor occurrence and development, has been widely attention. Targeted MDSCs therapy has a broad clinical application prospects, it is the hotspot in the study of tumor treatment. IL-6 is an important medium of mediated MDSCs differentiation, previous research found that L-4F, ApoA-I mimetic peptide, is an effective anti-angiogenesis and anti-inflammatory peptide, it can obviously reduce the secretion of inflammatory cytokines IL-6 et al. However, its regulation function of MDSC is unclear. Our previous research found that L-4F has not obviously anti-tumor effect, but it could decrease the infiltration of inflammatory cytokines-producing cells and MDSCs, meanwhile, L-4F obviously inhibit the angiogenesis. There by, we speculate that L-4F can suppress the development of pancreatic cancer through modulating MDSCs and anti-angiogenesis. In this study, we will explore the modulation of L-4F in MDSCs, and research the therapeutic roles and mechanism of L-4F in pancreatic cancer. Attempting to come up with a new ideas, that about the role of L-4F in the prevention and control pancreatic cancer, and lay the theoretical foundation for clinical pancreatic cancer immune therapy and new drug research and development.

胰腺癌是癌症之王，对传统的放化疗均不敏感，无有效治疗药物。因此迫切需要开发新的治疗方法。髓系抑制性细胞（MDSCs）可介导肿瘤免疫逃逸，促进肿瘤发生发展，因此针对MDSCs的免疫治疗具有广阔的临床应用前景，是肿瘤免疫治疗研究热点。IL-6是介导MDSCs分化的重要因子。载脂蛋白A-I模拟肽L-4F是抗血管生成和抗炎肽，可明显降低IL-6等炎症因子分泌。但其对MDSC的调控作用尚不清楚。我们研究发现L-4F体外无明显抗癌作用，但体内可抑制小鼠胰腺癌生长和肿瘤内IL-6等炎症因子分泌及免疫细胞浸润，同时MDSCs下降，肿瘤血管生成减少。因此，我们推测L-4F可能通过对MDSCs和肿瘤血管生成双重抑制作用抑制胰腺癌发生发展。本项目将研究L-4F对MDSCs等细胞的免疫调节及胰腺癌治疗的作用和分子机制，以期全面揭示L-4F及载脂蛋白A-I的免疫调节作用和抗癌机理，为胰腺癌临床免疫治疗开辟新的途径。

胰腺癌是人类恶性程度最高的肿瘤之一，是预后最差的肿瘤。化疗是中晚期胰腺癌患者主要的治疗手段，但传统的化学治疗效果并不理想，且存在严重的全身不良反应。为此，寻求新的、有效的胰腺癌治疗手段已成为广大医学工作者共同努力的方向。近年来胰腺癌的免疫治疗研究亦受到越来越多的重视。L-4F是根据载脂蛋白A-I（ApoA-I）的生物特性，设计出的由18个氨基酸组成的具有双亲性的模拟肽，保留了ApoA-I的抗炎活性。本研究构建小鼠原位胰腺癌模型，通过体内、体外实验，验证了L-4F可明显抑制小鼠胰腺癌的发展，且与以下机制相关①L-4F可抑制胰腺癌肿瘤组织内炎症细胞，包括IL-17A, IL-4, GM-CSF, IL-1β和IL-6分泌细胞、Th1和Th2细胞的浸润情况；②L-4F可抑制肿瘤相关巨噬细胞（TAM）特别是M2的浸润、极化及其相关功能；③L-4F可抑制中性粒细胞型-髓系抑制性细胞（PMN-MDSCs）的浸润、极化和其抑制T细胞的功能；④L-4F可抑制小鼠胰腺癌肿瘤组织血管生成情况。另外，本研究还探讨了L-4F作用于TAM和PMN-MDSCs的分子机制：①L-4F可明显上调LPS刺激的RAW264.7细胞的STAT3的磷酸化，并同时下调JNK和p38的磷酸化，而对ERK信号通路无影响；②L-4F可下调PMN-MDSCs细胞STAT3的磷酸化。本研究最终阐明了L-4F抗肿瘤作用的免疫细胞和分子机制，为探寻胰腺癌防治的新策略提供了科学依据。