独创性MyD88抑制剂抑制MDSCs功能以阻断肠道慢性炎症的恶性转化

Colitis-associated cancer (CAC) is commonly related with developing tumors avoiding immune destruction by inducing an immunosuppressive environment permissive to the emergence of immune-resistant cancer cell variants. The recognition of tumor escape from immune elimination as an emerging additional hallmark of cancer and the recovery of the capable of orchestrating efficient antitumoral immune responses have constituted one of the major paradigm shift in the field of prevention from CAC development. It is now evident that immune responses in cancer are negatively regulated by immunosuppressive cells, mainly myeloid-derived suppressor cells (MDSCs). They are largely responsible for inhibiting host T-cell activity against tumor-associated antigens and consequently impair the effectiveness of anticancer immunotherapeutic approaches. Therefore, a better understanding of the local tumour microenvironment and the exact mechanisms of induction and/or expansion of MDSCs in the tumour milieu should provide opportunities for testing novel treatments that target such cells and alter the balance in favour of more effective antitumour immune responses. This could also be vital for the design of more effective immunotherapeutic strategies. Nowadays, it is proved that the activation and the immune responses suppression of MDSCs is TLR-MyD88 signaling pathway- dependent. Subsequently, a kind of novel synthetic small molecule inhibitor of MyD88 - TJ-M2010 is designed and synthesized in our institute. We have proved that in a mouse model, the development of CAC can be successfully prevented by TJ-M2010-treatment. In this project the primary goal is to firstly clarify the mechanism of TJ-M2010 in CAC treatment, and secondly to define the mechanisms of signaling pathway of MDSCs in the process of CAC and the responsibility of MDSCs for inducing the tumor immune escape.

肠炎相关结肠癌（CAC）的发生与宿主免疫重建和肿瘤细胞免疫逃逸密切相关。骨髓源抑制性细胞（MDSC）是一种重要的参与炎症及肿瘤局部免疫微环境构建的细胞，抑制其免疫抑制功能，打破其介导形成的免疫抑制微环境，能够促进抗肿瘤免疫，防治肿瘤发生。然而MDSC介导CAC发生的分子机制还未明确。研究证明MDSC的功能与MyD88信号通路激活相关。我们针对MyD88分子结构域，合成了一种具有自主知识产权的小分子抑制剂TJ-M2010，申请人已发表成果证实，此MyD88抑制剂能够防治小鼠模型中CAC的发生，在此基础上，我们预测MDSC内MyD88信号通路激活在CAC发展时发挥重要作用。本项目旨在深入研究此独创性MyD88抑制剂对CAC肠道微环境中MDSC功能的影响，以期阐明其防治CAC的机制，同时进一步明确MDSC内MyD88信号通路在CAC发展过程中的重要作用，以揭示MDSC介导CAC发生的分子基础。

背景：目前骨髓源抑制性细胞（MDSC）被证实参与构建了肿瘤的抑制性免疫微环境而介导肿瘤的免疫逃逸。清除MDSC为肿瘤的免疫治疗提供了可行性的理想靶标。然而，关于MDSC介导的肿瘤免疫逃逸的确切分子机制知之甚少。方法：我们使用了新型MyD88抑制剂TJ-M2010-5来阻断MyD88信号传导，以防止小鼠肠炎相关结肠癌（CAC）的发展。结果：在这项研究中，我们证明CAC的防治与MDSC的生成、扩增减少及其免疫抑制功能被抑制相关，同时，抑制剂TJ-M2010-5的抗肿瘤作用取决于MyD88信号通路的激活。 MDSC的耗竭阻碍了MyD88抑制剂的抑瘤优势。此外，MyD88抑制剂治疗可降低CAC小鼠CD11b+ Gr1+ MDSC的蓄积，涉及与MDSC蓄积相关的细胞因子和生长因子（GM-CSF，G-CSF，IL-1β，IL-6和TGF-β）分泌减少，并降低与MDSC抑制功能相关的分子（iNOS，Arg-1和IDO）的表达。另外，在体外，MyD88抑制剂治疗降低了MDSC对活化的CD4+ T细胞增殖的抑制能力以及骨髓细胞分化为MDSC的能力。结论：MDSC是我们这种新型MyD88抑制剂防治CAC的主要靶细。我们的发现证明MyD88信号传导参与了MDSC免疫抑制功能。我们新型的MyD88抑制剂TJ-M2010-5是一种有效的调节MyD88信号传导的药物，其能够抑制MDSC介导的免疫抑制功能，从而促进新型抗肿瘤免疫治疗方法的发展。