2型神经纤维瘤病（NF2）是由NF2基因突变merlin蛋白功能缺失所致的多发肿瘤综合征，重型患者常因肿瘤发生过多无法治疗而早亡。我们在前期研究中发现6例重型NF2肿瘤中均存在PDL1的高表达和免疫微环境抑制，且它们与merlin蛋白磷酸化（p-merlin）水平密切相关。在肿瘤细胞中高表达p-merlin后PDL1表达调高，抑制其调控的PI3K/AKT/mTOR通路后PDL1表达调低。因而提出假设NF2肿瘤中p-merlin通过调控PDL1表达来介导免疫微环境抑制，在肿瘤的发生发展中起作用。首先，本课题拟研究不同NF2基因突变肿瘤中p-merlin对PDL1表达、免疫微环境和患者临床表型轻重的影响。其次，通过蛋白组学方法分析p-merlin调控PDL1的可能机制，并在标本中验证。进而在细胞和动物实验中探讨抑制各相关调控通路后对肿瘤免疫微环境的影响。本课题将对开展NF2免疫治疗奠定基础。

Neurofibromatosis type 2 (NF2) is a multiple tumor syndrome caused by NF2 mutation and merlin dysfunction. Severe-type NF2 patients usually die of unresectable multiple tumors. Our previous study found that sixe severe-type NF2 tumors all showed high expression of PDL1 and microenvironment immunosuppression. And they were highly related with merlin phosphorylation (p-merlin). In NF2 tumor cells, PDL1 expressed higher after up-regulation of p-merlin. PDL1 expressed lower after inhibition of PI3K/AKT/mTOR pathway regulated by p-merlin. We speculate that p-merlin affects the microenvironment immune status through regulation of PDL1 in NF2 tumors. In this study, we will confirm the regulation effect of PDL1, microenvironment immunosuppression, and clinical phenotype by p-merlin in NF2 tumors with various NF2 mutations. We will perform the proteomics analyisis to find possible pathways through which p-merlin regulates PDL1. These pathways will be confirmed in NF2 tumors. And they will be inhibited in cell and animal experiments to find the following effects on the tumor immune microenvironment. This study will lay the foundation for immunotherapy in NF2 tumors.