MiR-506诱导肿瘤相关巨噬细胞再极化抑制胰腺癌进展的机制研究

Immunosuppression of tumor microenvironment is a critical feature of pancreatic ductal adenocarcinoma (PDAC) and significantly contributes to its highly aggressive and rapid progressive characteristics. The infiltration of M2 (immunosuppressive type) tumor-associated macrophages (TAM) in tumor microenvironment is an important risk factor for the tumorigenesis, progression, metastasis and drug resistance of PDAC. In our previous research (published in Autophagy as the cover paper. IF: 9.1), we have found that miR-506 could not only induce autophagic cell death of pancreatic cancer cells but also decrease the ratio of M2/M1 TAM in PDAC microenvironment. MiR-506 exerts significantly immunoregulatory function but its associated mechanism was unclear. In this proposal, we will investigate: 1) The miR-506 expression in TAM, the proportion of TAM subsets and their correlation to the prognosis of PDAC patients; 2) Whether miR-506 affects the polarization of TAM in tumor microenvironment and inhibits the PDAC progression; 3) Whether miR-506 induces repolarization of M2 macrophage by directly targeting STAT3. This proposal will explore the expression and immune modulatory function of miR-506 in PDAC microenvironment, especially its impact on TAM polarization, and provide a new target for PDAC immunotherapy.

免疫抑制性肿瘤微环境是胰腺癌的重要特征，促进了其侵袭性高，进展迅速的临床特点。M2型(免疫抑制型)肿瘤相关巨噬细胞(TAM)在肿瘤微环境的浸润是胰腺癌发生、进展、转移和耐药的重要危险因素。申请人前期研究(第一作者发表于Autophagy, 封面文章, IF:9.1)发现：miR-506在诱导胰腺癌细胞自噬性死亡的同时，还可降低肿瘤微环境中M2/M1型TAM比例，具有免疫调节功能，但具体机制欠清。本项目拟在前期基础上：分析胰腺癌患者肿瘤组织TAM中MIR506表达，亚群比例变化与预后相关性；证实miR-506影响免疫微环境中TAM极化，抑制胰腺癌进展；进一步研究miR-506通过靶向STAT3诱导M2型巨噬细胞向M1型再极化的新机制。首次探索miR-506在胰腺癌免疫微环境特别是TAM极化过程中的表达变化和作用机制，为胰腺癌免疫治疗提供了新靶点。

胰腺癌侵袭性强，预后极差。肿瘤相关巨噬细胞主要为M2型巨噬细胞，具有强大的免疫抑制功能，在胰腺癌中发挥着重要的促肿瘤作用。MiR-506在多种恶性肿瘤中，通过多种途径发挥肿瘤抑制功能。在本研究中，我们推测miR-506可能通过诱导巨噬细胞再极化而发挥抗肿瘤作用。临床数据显示肿瘤组织低表达miR-506的胰腺癌患者预后更差，肿瘤微环境呈现免疫抑制性，特别是有更多的M2型肿瘤相关巨噬细胞浸润。小鼠模型显示miR-506可以抑制肿瘤进展并逆转其巨噬细胞依赖性的免疫抑制性肿瘤微环境。机制研究发现，miR-506可以通过直接靶向STAT3的方式诱导M2型巨噬细胞向M1型再极化。通过抑制或者基因下调STAT3表达也可获得同样的效果。MiR-506诱导再极化后的巨噬细胞可以降低小鼠肿瘤微环境中调节性T细胞浸润的比例，恢复被抑制的抗肿瘤T细胞免疫，还可增强抗PD1免疫治疗的功能。本研究将miR-506的抗肿瘤功能扩展至诱导巨噬细胞再极化，并且提示可将miR-506作为抗STAT3治疗应用于胰腺癌治疗。