mTOR-PP2A调控肿瘤相关巨噬细胞转化在胰腺癌中的作用研究

The microenvironment of pancreatic adenocarcinoma has a large infiltration of multiple types of immune cells, facilitating immune invasion and cancer progression. Tumor-associated macrophage (TAM) is one of the most important cell components among them. TAM is transformed from recruited peripheral monocytes under stimulation of various cytokines, but the underlying mechanism of its generation remains to be defined. Our previous studies suggested that mTOR signaling pathway and PP2A are involved in TAM transformation. Both activation of mTOR and inhibition of PP2A could enhance TAM generation. On the other hand, ample of evidence showed a negative regulation between PP2A and mTOR pathway. Thus, the current project plans to study the role of mTOR-PP2A in the regulation of TAM transformation, tumor immune invasion and cancer progression in pancreatic adenocarcinoma. The results can help to improve our understanding the mechanisms of TAM generation and to identify potential treatment target for TAM-based immunotherapy in pancreatic adenocarcinoma.

胰腺癌微环境中有大量的炎症、免疫细胞浸润，参与促进免疫逃逸和肿瘤进展，其中肿瘤相关巨噬细胞（Tumor-associated macrophage, TAM）是构成胰腺癌微环境的最重要成分之一。TAM由外周血募集的单核细胞转化而来，但调控其转化的分子机制缺乏深入认识。我们前期研究发现mTOR通路与PP2A均涉及TAM的转化，其中mTOR通路激活可以促进TAM生成，并增强肝癌中肿瘤血管生成；而下调PP2A活力也能够诱导TAM分化。另一方面，文献报道mTOR通路与PP2A存在负向相互调控作用，表明两者之前具有密切联系。故本课题拟以胰腺癌内的TAM为切入点，应用多种分子生物学技术和胰腺癌类器官及基因工程小鼠模型，研究mTOR与PP2A共同参与调控胰腺癌中TAM转化的作用机制以及对肿瘤免疫耐受微环境、肿瘤进展的影响，以期从中寻找新的潜在干预靶点，为基于TAM的胰腺癌免疫治疗提供新的解决途径。

肿瘤相关巨噬细胞（Tumor-associated macrophages, TAM）是胰腺癌免疫微环境中的重要组成部分，TAM在向M2表型转换后促进血管生成以及免疫逃逸。本课题目的在于探讨TAM表型转换调控的机制以及其对胰腺癌的相应作用。mTOR通路的激活在胰腺癌TAM发生M2转化过程中起到了关键作用，小鼠骨髓来源单核细胞诱导巨噬细胞后，给予mTOR通路抑制剂可以逆转M2表型的转化，降低IL-10表达、增加IL6、IL12表达。小鼠胰腺癌细胞皮下荷瘤模型中，mTOR抑制剂雷帕霉素降低巨噬细胞向肿瘤浸润，促进T细胞在肿瘤内富集，并增强PD-1抑制剂的疗效。此外，胰腺癌细胞坏死产生的碎片可通过激活TLR4/TRIF/NK-κB信号通路诱导M2型巨噬细胞分泌IL-1β。IL-1β可进一步促进胰腺癌发生上皮-间质化转变和转移。小鼠胰腺癌原位荷瘤模型中，给予COX-2抑制剂拮抗IL-1β诱导的炎症反应可增强吉西他滨的治疗效果并抑制转移发生。