卢斌峰教授和蒋敬庭博士自2006年开启持久而富有成效的合作，卢斌峰团队专注于寻找介导肿瘤免疫应答的关键调控分子，蒋教授团队在国内率先开展了肿瘤细胞免疫治疗并侧重于对接受过继性T细胞治疗的患者的临床研究。IL-33信号介导的生物学活性参与了炎症和多种免疫病理过程，而其在Th1型肿瘤免疫应答中的作用迄今不明。双方前期研究发现，肿瘤浸润CD8+T细胞高表达IL-33受体ST2；IL-33协同TCR及IL-12促进效应性CD8+T细胞分泌IFN-γ；小鼠B16移植瘤模型中IL-33延缓肿瘤生长。本项目拟以此为切入点，结合申请人的基础免疫学知识和合作者临床免疫治疗的经验，着重探讨1）IL-33是否直接促进人T细胞介导的免疫应答；2）借助人源化荷瘤小鼠模型研究IL-33介导的抗肿瘤免疫应答效应及机制，为将IL-33信号途径运用于肿瘤免疫治疗的临床转化研究奠定基础，为肿瘤细胞免疫治疗提供新的手段和策略。

Dr. Binfeng Lu’s research has helped elucidating molecular and cellular mechanisms controlling Th1 and CD8 T cell-mediated immune responses in the context of antitumor immunity. Dr. Lu’s group has discovered that the Gadd45/p38 signal transduction pathway plays a key role in tumor immunity. Dr. Lu’s group contributes to the understanding of cellular regulatory mechanisms within T cells by showing that autophagy is induced upon T cell activation and play important role in regulating T cell death. Dr. Lu’s laboratory has also revealed a key role of transcription factors T-bet and Eomes in promoting the function and trafficking of tumor-specific CD8 T cells and thereby promoting antitumor immunity. His group’s most recent interest is to identify factors that either promote or inhibit antitumor immunity and found that T-bet upregulated IL-33 receptor in T cells and IL-33 promoted effector functions of CD8 T cells. They have also discovered that TIM-3 is expressed on regulatory T cells and is a negative regulator of antitumor immunity in human lung cancer. Dr Lu’s group have consistently published in reputable journals and continuously received research support from NIH and various private research foundations...Since 2006, Dr. Lu has been collaborating with Dr. Jiang’s group at Soochow University. Dr. Jiang’s team has a lot of experiences with immunotherapy in China and their publications have demonstrated the efficacy and safety of adoptive T cell therapy in combination of chemotherapy for the late stage gastric and lung cancers. The two research groups have co-published 5 research papers and 2 review papers. These collaborative efforts pave the way for further joint research focusing on human tumor immunology. The proposed project will draw strength from Dr. Lu’s strength in tumor immunology and Dr. Jiang’s clinical strength in immunotherapy...In the current grant proposal, we will study how IL-33 boosts antitumor immunity in man and humanized mouse tumor models of immunotherapy. Interleukin-33 is a member of the IL-1 family of cytokines and is released by necrotic cells or activated innate immune cells such as macrophages during trauma or infection. We have recently found that ST2, a receptor for IL-33, is highly expressed in CD8 tumor infiltrating lymphocytes (TILs) as well as CD8 T cells cultured in Th1 conditions. Importantly, we have demonstrated that IL-33 synergized with TCR or IL-12 in increasing both human and mouse CD8 T cell functions such as IFNgamma production. The expression of IL-33 in mouse B16 melanoma cells potently inhibits tumor growth in mice. We will initiate two lines of research to further explore the role of IL-33 in antitumor immunity in human-relevant systems. 1. To test whether IL-33 directly promotes human type 1 lymphocyte-mediated immune responses. 2. To study the antitumor mechanisms through targeted delivery of IL-33 to human tumor sites using humanized mouse model..

IL-33属于白细胞介素1（Interleukin 1,IL-1）细胞因子家族成员。组成性表达于一些构成了我们机体第一道防御的上皮及内皮细胞。除此之外，还表达于一些坏死的细胞及活化的免疫细胞，如巨噬细胞在受到外源性感染的时候。尽管IL-33已经被证实诱导了Th2免疫应答，但其在Th1免疫应答中的作用仍不清楚。我们最近的研究发现，IL-33的受体ST2表达于效应性CD8+ T细胞，并且受T-bet调控，且IL-33可提高效应性CD8+T细胞的功能。因此，IL-33具有潜在抗肿瘤作用。本项目重点研究IL-33对肿瘤微环境的影响及其抗肿瘤作用。结果表明，B16-IL-33肿瘤在C57B/L6小鼠生长速度显著减慢。与B16-mock肿瘤相比，B16-IL-33肿瘤浸润CD45+、CD8+ T细胞、NK细胞比例明显增高。并且，B16-IL-33肿瘤浸润的CD8+ T细胞，NK细胞分泌细胞因子IFN-γ的能力更高。在缺失了转录因子T-bet及Eomes的小鼠中，B16-IL33肿瘤的生长速度显著增快，并且，与接种了B16-IL-33肿瘤细胞的野生型（WT）小鼠相比，肿瘤组织中浸润的CD45+、CD8+ T细胞、NK细胞比例明显减少，并且分泌细胞因子IFN-γ的能力降低。因此，IL-33明显提高了肿瘤微环境中Th1型免疫应答，具有潜在的抗肿瘤作用，为肿瘤免疫治疗提供了新思路和新策略。