口腔癌细胞源性外泌体-miRNAs调控NK细胞免疫活性的机制

Tumor-derived exosomes (TDEXs) have been reported to carry biological active molecules and factors which were able to regulate functions of immune cells. However, the detailed mechanism remains unclear, especially in NK cells. Exosomes are nanometric membrane vesicles secreted by almost all kinds of cell types, including cancer cells. One of their most intriguing roles is intercellular communication-exosomes function as the messengers, delivering various effectors or signaling macromolecules between specific cells. Our previous results showed that: The number of NK cells in peripheral blood was significantly correlated with the clinical phenotype of oral cancer patients; The exosomes derived from oral cancer cells can enter NK cells by endocytosis; The exosomes derived from oral cancer cells can regulate the gene expression of NK cells. Based on these results, we speculated that the exosomal miRNAs derived from oral cancer cells may play an important role in the regulation of NK cell immune activity. In this study, we choose the tumor microenvironment as our study scopes, and mainly focus on the mechanism of immunomodulatory mediated by the exosomal miRNAs derived from oral cancer cells. This study will facilitate to provide some strategies for cancer therapy based on exosomes. In addition, exosomes also can be designed to be a drugs-delivering vector for cancer therapy.

肿瘤细胞来源的外泌体（TDEXs）在肿瘤免疫中具有重要的调控作用，目前有关外泌体在肿瘤免疫调控中的作用机制尚不明确，特别是在NK细胞抗肿瘤免疫领域。外泌体是细胞分泌的一种小囊泡结构，包含多种miRNAs，可以在遗传信息层面介导不同类型细胞之间进行信息交流。我们前期实验表明：口腔癌患者外周血中NK细胞的数量及免疫活性与临床表型显著相关；口腔癌细胞源性外泌体被NK细胞内化后可以调控NK细胞的基因表达及其免疫功能。基于以上结果，我们推测：口腔癌细胞源性外泌体-miRNAs在NK细胞的免疫活性调节方面具有重要作用。本研究以口腔癌细胞源性外泌体-miRNAs为主要研究对象，探究外泌体-miRNAs在调控NK细胞免疫活性方面的作用机制。通过临床样本及PDX模型评估外泌体-miRNAs作为口腔癌诊治靶标的可行性。该问题的解决将为以外泌体为诊治靶点的治疗手段提供科学依据。

肿瘤细胞来源的外泌体（TDEXs）在肿瘤免疫中具有重要的调控作用，目前有关外泌体在肿瘤免疫调控中的作用机制尚不明确，特别是在NK细胞抗肿瘤免疫领域。外泌体是细胞分泌的一种小囊泡结构，包含多种miRNAs，可以在遗传信息层面介导不同类型细胞之间进行信息交流。项目组的研究表明：口腔癌患者外周血中NK细胞的数量及免疫活性与临床表型显著相关；口腔癌细胞源性外泌体被NK细胞内化后可以调控NK细胞的基因表达及其免疫活性。研究进一步证实，口腔癌细胞源性外泌体-miRNAs在NK细胞的免疫活性调节方面具有重要作用。项目组先后完成了如下相关工作：① 证实了口腔癌细胞来源的外泌体通过NAP1蛋白调控NK细胞免疫活性的机制；② 证实了CAFs细胞衍生的IL-6通过PDPN促进口腔癌进展的机制；③ 阐明了lncRNA PANDAR通过竞争性结合p53蛋白调控CDKN1A基因表达，促进肿瘤进展的机制；④ 首次鉴定了分泌型蛋白激酶p85S6K1促进肿瘤细胞迁移和生长的作用与机制；⑤ 证实了CAFs细胞来源的Exo-miR-196a调控口腔癌细胞顺铂耐药的机制；⑥ 证实了CFAs来源的Exo-miR-3188通过BCL-2促进头颈鳞癌进展的机制；⑦ 证实了lncRNA LINC00460通过诱导peroxiredoxin-1进入细胞核，促进口腔癌细胞发生EMT的机制；⑧ 证实了lncRNA KTN1-AS1通过竞争性结合miR-153促进口腔鳞癌恶性进展的机制；⑨ 深入阐明了VN1R5通过增强DNA损伤修复活性促进口腔鳞癌顺铂耐药的机制。通过大样本临床样本及PDX动物模型评估了外泌体-miRNAs等作为口腔癌诊治靶标的可行性。该问题的解决将为以外泌体为诊治靶点的治疗手段提供科学依据。