髓源性抑制细胞(MDSC)在免疫应答中发挥重要的调控作用，探讨肿瘤微环境中MDSC免疫抑制性功能的调控对于寻找肿瘤免疫治疗靶点具有重要意义。TIM-3是一个重要的免疫抑制分子，而TIM-3是否参与MDSC功能的调控尚未明确。我们前期研究发现TIM-3在小鼠荷瘤模型与人结直肠癌组织MDSC上诱导性表达，体外单抗阻断实验提示TIM-3与MDSC的分化与功能相关。本课题将探讨TIM-3在结直肠癌组织MDSC上表达的特征与意义，研究TIM-3在MDSC上表达的调节机制；采用组织特异性基因敲除等技术阐明TIM-3对MDSC扩增、分化及其功能的影响；并在免疫治疗模型中验证TIM-3调控MDSC功能影响抗肿瘤免疫应答的作用；进一步揭示TIM-3调控MDSC抑制功能依赖的关键分子，为肿瘤免疫治疗提供新的理论依据。

Accumulating evidence suggests that myeloid-derived suppressor cells (MDSC) play a key role in immune responses. Thus, finding new molecules that regulate MDSC differentiation and immunosuppressive function should provide new targets for cancer immunotherapy. TIM-3 is an important immune inhibitory molecule. Whether TIM-3 is involved in modulation of immune suppressive function of MDSC is still unknown. Our preliminary study shows that TIM-3 was inducibly expressed on MDSC in tumor-bearing mice model and colorectal cancer patients. Our preliminary data using neutralizing TIM-3 mAb in vitro suggests that TIM-3 was associated with the differentiation and suppressive function of MDSC. Based on these findings, we hypothesize that TIM-3 inhibits antitumor immune responses through regulating the function of MDSC. To test this hypothesis, we will study the characterization and clinical significance of TIM-3 expression on MDSC in patients with colorectal cancer. In addition, we will discern cytokines that are involved in the induction of TIM-3 expression on MDSC. Futhermore, we will determine the effect of TIM-3 on proliferation, differentiation and suppressive function of MDSC, and to examine whether TIM-3 inhibits antitumor responses through regulating the activation of MDSC in adoptive immunotherapy mice model; finally, we will explore the molecular regulatory mechanisms of TIM-3 on MDSC. These studies will shed light on new targets for immunotherapy of cancer.