荷瘤状态下促瘤中性粒细胞对NK细胞抗肿瘤功能的抑制作用及其机制

项目名称： 荷瘤状态下促瘤中性粒细胞对NK细胞抗肿瘤功能的抑制作用及其机制

项目编号： No.81502461

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 孙锐

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 肿瘤中自然杀伤细胞（NK）的抗肿瘤功能减弱，其机制未完全阐明。我们研究发现：荷瘤状态下，中性粒细胞（PMN）的功能转变为促肿瘤生长，促瘤生长的PMN又可导致NK的抗肿瘤功能下降，提示促瘤PMN对NK功能的抑制是NK功能异常的机制之一。同时观察到：促瘤PMN可逆转为抑瘤细胞，且需要在正常NK的协同下才可发挥较强的抗肿瘤功能，而NK功能异常将是PMN与NK协同抗肿瘤功能的瓶颈。本项目将探索PMN介导的NK功能异常的物质基础（NK激活/抑制性受体、细胞毒性分子，趋化、激活能力，成熟状态等的改变），研究PMN削弱NK功能的分子机制及作用形式，并研究NK激活剂IL-2、IL-18、IL-15及CD40抗体等对异常功能NK细胞功能恢复的作用。本项目有望阐明PMN介导的NK功能异常的机制，具有重要的理论价值，可为建立荷瘤状态下以逆转PMN功能为基础、联合恢复NK功能的肿瘤免疫治疗提供思路和依据。

中文关键词： 自然杀伤细胞；中性粒细胞；促瘤；细胞毒性；免疫治疗

英文摘要： A weaker antitumor capability of NK cells was found in many types of human cancers and murine models, and the mechanisms were not completely elucidated. In our recent studies, we found that the function of polymorphonuclear leukocytes (PMNs or neutrophils) was converted from tumor-suppressing to tumor-promoting in tumor-bearing status, and these PMNs could weaken the antitumor capability of NK cells. Meanwhile, we also found that the tumor-promoting PMNs can be reversed to tumor-suppressing cells, and normal NK cells are required for better antitumor efficacy based on the PMNs function reversion, so the weaker antitumor capability of NK cells might be the bottleneck of synergistic antitumor function of PMNs and NK cells. In this project, we will investigate the material basis (including the expression of NK activating/inhibitory receptors, cytotoxicity molecular; the capability of chemotaxis and activation; the maturation status) of decreased antitumor capability of NK cells. Meanwhile, the molecular mechanisms of how PMNs inhibit NK cells will be also investigated. In additional, we will further investigate the effect of NK activating factor IL-2, IL-18, IL-15 and anti-CD40 antibody on the recovery of NK cells function. Our study is expected to clarify the material basis and mechanism of NK cells dysfunction mediated by tumor-promoting PMNs. The results may not only be important for the theory of immunoregulation, but also lead to a new strategy of tumor therapy by recovering the antitumor function of neutrophils and NK cells together in presence of tumor.

英文关键词： nature killer cells;neutrophils;tumor-promoting;cytotoxicity;immunotherapy