肿瘤细胞/靶细胞在与免疫细胞形成cell-in-cell结构中的作用及其机制研究

近年研究显示肿瘤细胞能内化活的免疫细胞，形成异质性cell-in-cell(CIC)结构，导致免疫细胞死亡。因此，该过程被认为是一种新的免疫逃逸机制。在CIC结构形成过程中, 传统观点认为免疫细胞作为效应细胞是主动进入肿瘤细胞（靶细胞），单向主导驱动该过程的完成，而对靶细胞的作用及机制缺乏重视与研究。我们前期研究发现，不同的肿瘤细胞与同一免疫细胞形成CIC结构的效率存在明显差异，提示作为靶细胞的肿瘤细胞在CIC形成过程中也发挥着重要作用。本研究拟利用已建立的异质性CIC结构模型，通过条件优化后的双色流式细胞分选技术富集CIC形成能力强的肿瘤细胞，进而用表达谱分析鉴定调控CIC形成的关键分子，利用动态显微成像等多种方法研究该分子调控CIC结构形成的分子和细胞生物学机制，探讨其在肿瘤免疫逃逸中的作用。旨在揭示靶细胞调控异质性CIC结构形成的作用机制，为打破免疫逃逸及肿瘤治疗提供新的思路及策略。

Recently, viable immune cells such as NK cells were found entering tumor cells to form so called heterotypic cell-in-cell structures, which will eventually lead to the death of some internalized cells. This process was therefore regarded as a new mechanism of immune evasion. However, the molecular and cellular mechanisms underlying the structure formation are largely unknown, probably due to lack of proper research methods and models. Although immune cells were currently thought to actively control their invasion into the tumor cells, our preliminary data showed that tumor cell also played active role in the formation of the heterotypic cell-in-cell structures, which promotes us to explore it underpinning mechanisms. In this project, by utilizing a model currently accepted for studying heterotypic cell-in-cell structures, we attempt to enrich tumor cells with higher abilities to internalize immune cell through flow cytometry sorting, followed by expression profiling to identify key regulators, whose roles in cell-in-cell formation and immune evasion as well will be investigated via multiple methods, including live-cell imaging and the like. As a result, we expect to establish the role of target cells (tumor cells) in forming heterotypic cell-in-cell structures and decipher its underlying mechanisms, based on which novel therapeutic strategies could be developed by targeting immune evasion.