NLRP3突变型肺癌的发生发展及免疫逃逸机制研究

Genomic mutation-based targeted and immunotherapy are promising treatments for advanced lung cancer. The role of inflammasome in the tumor immune response and tumor immune escape and has received increasing attention. Gain-of -function mutations in NLRP3 make the spontaneous activation of NLRP3 inflammasome and continuous secretion of IL-1 beta, leading to the remodeling of tumor inflammatory microenvironment and immunological suppression. Our preliminary study showed that NLRP3 mutation accounted for 13.7% of lung cancer, but the unique tumorigenesis, progression and immune escape of NLRP3 mutated lung cancer are still unclear. Using Lewis lung cancer mice model, we will investigated the growth,invasion and metastasis charcristics of NLRP3 mutated lung cancer, and illustrate the mechanisms of tumor immune escape NLRP3 mutated lung cancer,mediated by MDSC or Treg via NLRP3/IL-1 beta/IRAK-1 axis, as well as inhibitory costimulatory molecules PD-L1and CTLA4. Furthermore,this proposed mechanism of immunity escape will be verified in the humanized NOD/SCID/IL2R γ-null mice tumor xenograft model. This project will give novel insights for tumor immunology of NLRP3 mutated lung cancer,and provide new evident for the target molecules in treatment of NLRP3 mutated lung cancer.

基于分子分型的个体化靶向和免疫治疗是攻克晚期肺癌的希望，炎性体在肿瘤免疫应答和免疫逃逸中的作用日益受到重视。功能获得性NLRP3突变所导致的NLRP3炎性体自发性激活和IL-1β的持续分泌，并引起肿瘤炎性微环境的重塑并介导免疫逃逸。项目组前期研究结果表明NLRP3突变占到肺癌的13.7%，NLRP3突变型肺癌的独特发生、发展及其介导免疫逃逸的机制尚有待于研究。本项目以小鼠lewis肺癌为模型，研究NLRP3突变型肺癌的生长，侵袭转移等肿瘤生物学特性， 通过体外、体内及干预实验，阐明NLRP3mut/ IL-1β通过上调髓源抑制性细胞、调节性T细胞和抑制性共刺激分子PD-L1、CTLA4来介导肿瘤免疫逃逸的机制，并用人源免疫化NOD/SCID/ IL2Rγnull小鼠移植瘤模型进行机制验证。有助于从全新角度理解肺癌与免疫的相互作用，为将来NLRP突变型肺癌的靶向或免疫治疗提供理论依据

基于分子分型的个体化靶向和免疫治疗是攻克晚期肺癌的希望，炎性体在肿瘤免疫应答和免疫逃逸中的作用日益受到重视。功能获得性NLRP3突变所导致的NLRP3炎性体自发性激活和IL-1β的持续分泌，并引起肿瘤炎性微环境的重塑并介导免疫逃逸。项目组前期研究结果表明NLRP3突变占到肺癌的13.7%，NLRP3突变型肺癌的独特发生、发展及其介导免疫逃逸的机制尚有待于研究。本项目以小鼠lewis肺癌为模型，通过体外、体内实验研究NLRP3突变型肺癌肿瘤生物学特性，阐明NLRP3mut/ IL-1β通过上调髓源抑制性细胞、调节性T细胞和抑制性共刺激分子PD-L1、CTLA4来介导肿瘤免疫逃逸的机制，收集1000余例肺癌临床病例，研究IL-1β、IL-6对预后的影响。结果表明，我们成功建立了NLRP3突变型体内外小鼠Lewis肺癌模型，证实了NLRP3突变促进肺癌生长，激活IL-1β/IRAK-1 通路，上调IL-1β、IL-6表达，诱导和招募外周血和肿瘤微环境中MDSC(髓源抑制性细胞)、Treg ，上调其抑制性共刺激分子PD-L1、CTLA4 ,证实了共刺激信号分子ICOS/ICOSLG参与这一过程。临床病例研究中我们收集了707例晚期小细胞肺癌及324例手术肺腺癌患者，结果表明IL-1β、IL-6是肺癌预后的独立影响因子，高表达IL-1β、IL-6的患者总生存期短。本研究初步揭示了NLRP3在肺癌免疫逃逸中的作用及其机制，为将来NLRP3突变型肺癌免疫治疗提供了理论依据。