教育经历
2012.07-2017.09 美国MD安德森癌症中心 博士后 2004.09-2009.07 北京协和医科大学&中国医学科学院 药物研究所 药理学系 博士 1997.09-2002.07 中国药科大学 药理学系 学士
B.S. in Pharmacology, China Pharmaceutical University (1997.09-2002.07) Ph.D. in Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College (2004.09-2009.07) Postgraduate Training Postdoc Fellow, Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center (2012.07-2017.09)
工作经历
2019.12 -至今 首都医科大学 北京脑重大疾病研究院 神经免疫实验室 教授 2017.10-2019.11 美国MD安德森癌症中心 研究科学家
Research Scientist, Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center (2017.10-2019.11) Professor, Beijing Institute of Brain Disorders, Capital Medical University (2019.12-present)
研究概述
炎症反应在肿瘤的发生、发展和转移的各阶段都是至关重要的，倾向于促进肿瘤。肿瘤的免疫炎症反应与机体发育、免疫、维持组织内环境稳态或组织修复中的炎症反应具有相似性。然而组织保护性和致瘤性炎症之间又有明显的区别，包括时空性的差异。阐明组织保护性和致瘤性炎症的差别、揭示调控促肿瘤炎症的分子和细胞机制的研究，将是进一步发展抗癌治疗的关键。 本人聚焦免疫炎症与肿瘤发生、发展和转移之间的关系，主要探讨肿瘤中炎症与组织损伤修复炎症的相似性和差异性，以及免疫炎症驱动肿瘤发生、进展和转移的分子细胞机制。从微环境中的先天性免疫信号TLRs、免疫细胞巨噬细胞和NKT细胞，到获得性免疫的免疫监测点分子、效应T细胞、Treg细胞等，以及先天性免疫和获得性免疫的桥梁抗原呈递细胞等，研究影响免疫调控网络和肿瘤发生发展的机制，以及研究肿瘤细胞通过产生免疫调控分子调控免疫抑制微环境促进自身发展的机制，系统性的揭示了免疫炎症与肿瘤之间的关系，取得了系列创新成果；发现FGL2是胶质瘤不良预后的危险因素，是调控胶质瘤免疫抑制微环境的关键分子之一，并阐明其调控机制；进一步证明FGL2是治疗胶质瘤的潜在靶点，在此基础上开发了靶向FGL2的治疗性抗体用于治疗胶质瘤；发现先天性免疫信号TLRs在肿瘤发生和转移中的时空效应，揭示TLRs介导的免疫-自噬反应参与肿瘤发生和转移的直接作用机制，为应用TLRs激动剂和阻断性抗体治疗肿瘤提供理论依据和治疗策略；发现并阐明TLR2/4信号在炎症引起的组织损伤和修复中的作用和机制；建立了炎症损伤时治疗靶点——损伤相关模式分子HMGB1抑制剂的筛选平台，筛选出抑制HMGB1活性的候选化合物；发现急慢性损伤时IL-30通过调控NKT细胞抑制急性炎症损伤和改善损伤修复的作用及机制。这些研究成果得到包括欧美等国院士在内的国际同行正面引用和评价，被写入丛书或专著等20多部，为深入研究肿瘤发生发展的免疫学机制奠定了坚实的基础，为开发肿瘤的免疫治疗新方法提供了理论依据，并筛选和研发多个具有临床转化价值的先导物。 目前的研究兴趣是免疫生物学和免疫治疗，主要是中枢神经系统和免疫系统相互作用的机制和开发相关疾病的免疫新疗法。主要研究领域为：脑肿瘤免疫反应的特点和机制及免疫治疗药物的研发；代谢免疫参与脑肿瘤发生发展的作用和机制；免疫对中枢神经系统损伤和修复的影响和作用机制。
Research Summary I have been working to figure out the function and mechanism of immune response on tumor development and progression, also discovering and developing immunotherapeutic drugs or strategies for treatment during the past twelve years, the main achievements are: 1) FGL2 mediates immune tolerance in brain microenvironment, promoting glioma development, progression, and malignant transformation. FGL2 is a key hub of tumor-mediated immune suppression in GBM by regulating expression of immune checkpoints and augmenting intratumoral skewing of Tregs, myeloid-derived suppressor cells (MDSCs), and M2 macrophages. FGL2 secreted from tumor cells is the primary suppressor of differentiation of antigen-presenting CD103+ DCs via blocking of GM-CSF signal transduction and subsequent T cell functions in the brain. FGL2 promotes tumorigenicity of glioma cells with similar stem-like phenotypes in vitro in an expression level dependent manner in immunocompetent mice. The boost effect of FGL2 on tumorigenesis depends on FGL2-wired macrophages in tumor microenvironment. 2) The TLRs play a role in tumor progression and treatment. Optimal synergistic combinations of immunotherapy should include components that can enhance the antitumor capability (TLR4/9 agonists) and components that can eliminate the tumor-promoting factors from the tumor environment. TLR2/4 signaling plays a critical role in the initiation and progression of hepatocarcinogenesis through regulating senescence or DNA damage-reparation response. 3) Inflammation induces organ injury by HMGB1 (damage-associated molecular patterns) and their receptors TLRs (Toll-like receptors) are the intrinsic initiators of inflammation after injury; IL-30 is a regulator to control acute inflammation and protect organs against inflammation-induced injury through regulating cytokines production profiles in NKT cells. Our laboratory is currently focusing on: 1. Mapping immune cells across the entire brain during glioma development and progression with different gene mutations, especially myeloid cells (macrophages, microglia, MDSCs, neutrophils, DCs, etc.), to identify and locate multiple distinct immune populations, to characterize the phenotype of immune cells and immune response profiles within brain, and to correlate immune response profiles with disease progression in animal models and clinical patients. 2. Understanding the biology and intracellular signaling properties of FGL2. Dissecting the mechanisms by which FGL2 mediates the immune suppression in diseases. 3. Investing metabolic and functional reprogramming of tumor cells and immune cells in brain tumor, identifying metabolic markers in tumors which correlates with tumor progression and prognosis, and finding novel therapeutic targets for brain tumors.
代表成果
★ 发表论文 1. Yan J#, Zhao Q, Wang J, Tian X, Wang J, Xia X, Ott M, Rao G, Heimberger AB, Li S. FGL2-wired macrophages secrete CXCL7 to regulate the stem-like functionality of glioma cells. Cancer Letters. 2021; 506:83-94. 2. Liu SS, Liu C, Lv XX, Cui B, Yan J, Li YX, Li K, Hua F, Zhang XW, Yu JJ, Yu JM, Wang F, Shang S, Li PP, Zhou ZG, Xiao Y, Hu ZW The chemokine CCL1 triggers an AMFR-SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis. Immunity. 2021; 54:1–15. 3. Yan J, Zhao Q, Gabrusiewicz K, Kong LY, Xia X, Wang J, Ott M, Xu J, Davis RE, Huo L, Rao G, Sun SC, Watowich SS, Heimberger AB, Li S. FGL2 promotes tumor progression in the CNS by suppressing CD103+ dendritic cell differentiation. Nature Communications. 2019;10(1):448. 4. Latha K*, Yan J*, Yang Y, Gressot LV, Kong LY, Manyam G, Ezhilarasan R, Wang Q, Sulman EP, Eric Davis R, Huang S, Fuller GN, Rao A, Heimberger AB, Li S, Rao G. The Role of Fibrinogen-Like Protein 2 on Immunosuppression and Malignant Progression in Glioma. JNCI J Natl Cancer Inst. 2019;111(3):292-300. 5. Mitra A, Yan J, Xia X, Zhou S, Chen J, Mishra L, Li S. IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2-spectrin+/− mice. Hepatology. 2017; 65(4): 1222-1236. 6. Yan J, Mitra A, Hu J, Cutrera JJ, Xia X, Doetschman T, Gagea M, Mishra L, Li S. Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells. Journal of Hepatology. 2016; 64(5):1128-36. 7. Hu J*, Yan J*, Rao G*, Latha K, Overwijk WW, Heimberger AB, Li S. The Duality of Fgl2-Secreted Immune Checkpoint Regulator Versus Membrane-Associated Procoagulant: Therapeutic Potential and Implications. International Reviews of Immunology. 2016; 35(4):325-339. 8. Yan J, Kong LY, Hu J, Gabrusiewicz K, Dibra D, Xia X, Heimberger AB, Li S. FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas. JNCI J Natl Cancer Inst. 2015;107 (8): djv137. 9. Yan J, Li S, Li S. The Role of the Liver in Sepsis. International Reviews of Immunology. 2014; 33(6):498-510. 10. Du D*, Yan J*, Ren J*, Lv H, Li Y, Xu S, Wang Y, Ma S, Qu J, Tang W, Hu Z, Yu S. Synthesis, Biological Evaluation, and Molecular Modeling of Glycyrrhizin Derivatives as Potent High-Mobility Group Box-1 Inhibitors with Anti-Heart-Failure Activity in Vivo. J. Med. Chem. 2013; 56(1):97-108.
★ 申请专利 1. Li SL, Yan J, Xia XQ, Hu JM, Zhao QN. Fgl2 monoclonal antibodies and their use in treating malignant tumors. U.S. Patent Application No. 62/501,870, (WO2018204928A1). 2. Hu ZW, Yan J, and Cui B. Traditional Chinese medicine composite for preventing or treating fibrosis diseases as well as preparation method and application of same. Chinese National Invention Patent (CN 201210183664). 2012. Patent Cooperation Treaty (WO2013181978 A1). 2013. 3. Hu ZW, Yan J, He LS, Cui B, et al. The application of combination of TLR4 and TLR9 agonists for inhibiting tumor metastasis. Chinese National Invention Patent (200610112299.5). 2006. 4. Du GH, Zhu HB, Zhang L, Yan J and Zang YQ. High throughput screening method of acyl coenzyme A-cholesterol acyltransferase inhibitors by detection the level of sulfydryl. Chinese National Invention Patent (200610092035.8). 2006.
★ 其它学术成就 学术任职 2021年 北京市药学会应用药理专业委员会 委员 Applied Pharmacology Committee of Beijing Pharmaceutical Association, Fellow 获得人才计划 2020年入选北京市第十五批次青年人才
