TIM-3调节MDSC功能及影响抗肿瘤免疫应答的机制

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.

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。

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。项目组发现射频消融(Radiofrequency ablation, RFA)治疗后期可引起肿瘤浸润T细胞活化后失能、Treg与MDSCs扩增、Th1/Th2应答转化及PD-1/PD-L1表达上调，可使大约30%的PD-L1阴性患者转化为阳性，使这部分患者从PD-1单抗的治疗中获益，提出RFA与PD-1单抗联合使用的结直肠癌肝转移精准免疫治疗新策略，具有重要临床应用价值，相关成果发表在国际著名期刊《Clinical Cancer Research》。项目组还评估了结直肠癌肝转移由于不完全的RFA（iRFA）而导致的残留肿瘤块的存在与转移和预后的关系。证明了iRFA会促进肿瘤进展并阻碍抗PD-1治疗的功效。iRFA可持续诱导局部髓样抑制细胞介导炎症反应，抑制肿瘤中的T细胞功能。源自肿瘤细胞的CCL2促进了单核细胞和肿瘤相关巨噬细胞等在肿瘤微环境的聚集并介导免疫抑制影响PD-1单抗疗效，相关成果发表在国际著名期刊《Nature Communication》。