Exosome介导的口腔鳞癌、MDSC、γδT细胞间信息传递在缺氧促进肿瘤侵袭转移中的作用及其机制

Tumor associated myeloid derived suppressor cells (MDSCs) could inhibit the cytotoxicity of T lymphocytes resulting escape of cancer cells from immune-surveillance. Circulating γδ T cells can kill cancer cell directly or indirectly, while γδ T cells derived from cancer micro-environment could induce cancer progression. The mechanism underlying this transition is not clear now. Recently, the discovery of exosome as a cargo of protein, mRNA, and microRNA provides a possibility that cancer cells, MDSC and γδ T cells may communicate and affect each other’s function through releasing exosomes. In this study, we are going to study whether the miRNA, mRNA, and protein cargos of exosome derived from OSCC, MDSC and γδ T cells could be affected by hypoxia. Using in vitro cell culture, animal model, and clinical sample, we will study which signaling pathway in OSCC, MDSC and γδ T cells could be affected by hypoxia exosomes; what function and biological behavior could be affected by hypoxic exosomes; and which cargo in the hypoxic exosomes play the key role in the regulation process. We will explore whether genetic engineered γδ T cell-derived exosome could be potentially used as immunotherapy weapon to treat OSCC. The results of this study will add new knowledge in the mechanism of how OSCC/MDSC/γδ T affecting each other in the tumor microenvironment to induce cancer progression, and provide novel insight in preventing metastasis of OSCC for clinicians.

MDSC可抑制T细胞抗肿瘤免疫功能，促进肿瘤侵袭转移。外周血γδ T细胞可以对肿瘤细胞发挥杀伤作用，而肿瘤微环境获得的γδ T细胞则促进肿瘤进展，其机制目前尚不清楚。exosome细胞间通讯媒介的发现为解释肿瘤微环境中OSCC/MDSC/γδ T细胞间信息交流相互影响对方功能提供了新思路。本课题拟在体外细胞、PDX模型和临床组织样本中，从exosome相关miRNA、mRNA和蛋白多角度出发，探讨缺氧对OSCC/MDSC/γδ T细胞及其携带的成份有何影响？缺氧exosome中哪些关键成份调控了OSCC/MDSC/γδ T细胞的哪些关键信号通路？同时影响了哪些生物学行为？基因工程改建γδ T来源的exosome能否作为抗肿瘤免疫治疗工具？研究结果将以exosome介导的细胞间信息传递的新视野，诠释缺氧微环境促进口腔鳞癌侵袭转移的机制，为临床防治口腔鳞癌侵袭转移提供新的思路和策略。

MDSC可抑制T细胞抗肿瘤免疫功能，促进肿瘤侵袭转移。外周血γδ T细胞可以对肿瘤细胞发挥杀伤作用，而肿瘤微环境获得的γδ T细胞则促进肿瘤进展，其机制目前尚不清楚。exosome细胞间通讯媒介的发现为解释肿瘤微环境中OSCC/MDSC/γδ T细胞间信息交流相互影响对方功能提供了新思路。本团队最新研究结果解释了缺氧肿瘤微环境中氧浓度在肿瘤细胞外泌体调控γδ T细胞免疫活性方面的作用，发现氧浓度扮演的开关的作用。常氧条件下γδ T 细胞正常发挥抗肿瘤免疫活性，但在缺氧微环境下γδ T 细胞的抗肿瘤免疫活性受到显著抑制，这种抑制作用的机制在于缺氧肿瘤细胞释放外泌体携带miR-21，传递至髓源抑制细胞（MDSC），并且通过miR-21/PTEN/PD-L1 途径增强了MDSC 细胞的免疫抑制能力，从而间接抑制乏氧微环境中γδ T细胞的抗肿瘤免疫活性。研究结果为临床防治口腔鳞癌侵袭转移提供新的思路和策略。