Smad4调控胰腺导管腺癌肿瘤免疫的功能和机制研究

Pancreatic ductal adenocarcinoma (PDAC) is malignant cancer and insensitive to immunotherapy. Smad4 (DPC4) gene is mutated in 55% PDAC patients, and contribute to resistance to radiotherapy and chemotherapy. However, the role of Smad4 in immunogenicity and immune microenvironment of PDAC tumors is still unclear. Our preliminary results showed that, in Smad4 knockout PDAC cells, DNA damage levels and proliferation rate in vitro was increased. In vivo the growth rate of Smad4-knockout PDAC-derived tumor was similar to wild-type PDAC cells when inoculated in T cell-deficient nude mice, but dramatically reduced in immunocompetent C57BL/6 mice. Furthermore, the growth rate of Smad4-deficient tumor was recovered to WT level when CD8 T cells were depleted in C57BL/6 mice. We hypothesize that Smad4 deficiency may increase tumor immunogenicity and change tumor microenvironment in vivo, and lead to enhanced tumor immune recognition and eradication. To test this hypothesis, we plan to identify the molecular mechanism by which smad4 regulates tumor immunogenicity and tumor microenvironment using gene knockout cells and mouse model. The outcome of this project will provide theoretical basis for finding a new anti-tumor immunotherapy methods for Smad4 mutant PDAC patients.

胰腺导管腺癌（PDAC）对免疫治疗不敏感，其机制可能与肿瘤免疫微环境有关。PDAC中Smad4基因突变率达55%，显著影响放化疗疗效，而此突变对PDAC免疫原性及肿瘤免疫微环境的影响还不清楚。本课题组前期工作发现，小鼠PDAC细胞敲除Smad4基因后，细胞内DNA损伤增加；在裸鼠中成瘤能力和野生型细胞接近，但在免疫系统健全小鼠体内成瘤能力明显减弱。清除小鼠体内CD8细胞后，Smad4敲除细胞的成瘤速度恢复到野生型的水平。故推测，肿瘤细胞体内外生长差异是因Smad4缺失增强肿瘤细胞免疫原性，改变了肿瘤免疫微环境，使肿瘤细胞更易被免疫系统识别清除。据此，我们提出科学问题：Smad4如何调节PDAC的免疫原性和免疫微环境？本项目拟利用基因敲除细胞及动物模型，阐明 Smad4影响PDAC免疫原性和肿瘤微环境的机制，为针对Smad4突变PDAC患者寻找新的肿瘤免疫治疗方法提供理论依据和临床前实验证据

胰腺导管腺癌（PDAC）对免疫治疗不敏感，其机制可能与肿瘤免疫微环境有关。PDAC中Smad4基因突变率达55%，显著影响放化疗疗效，而此突变对PDAC免疫原性及肿瘤免疫微环境的影 响还不清楚。本课题组前期工作发现，小鼠PDAC细胞敲除Smad4基因后，细胞内DNA损伤增加；在裸鼠中成瘤能力和野生型细胞接近，但在免疫系统健全小鼠体内成瘤能力明显减弱。清除小 鼠体内CD8细胞后，Smad4敲除细胞的成瘤速度恢复到野生型的水平。故推测，肿瘤细胞体内外生长差异是因Smad4缺失增强肿瘤细胞免疫原性，改变了肿瘤免疫微环境，使肿瘤细胞更易被免疫系统识别清除。据此，我们提出科学问题：Smad4如何调节PDAC的免疫原性和免疫微环境？本项目拟利用基因敲除细胞及动物模型，阐明 Smad4影响PDAC免疫原性和肿瘤微环境的机制，为针对Smad4突变PDAC患者寻找新的肿瘤免疫治疗方法提供理论依据和临床前实验证据。