T细胞免疫与肿瘤免疫治疗研究组

研究队伍

研究组长：刘龙超 研究员 博士生导师

电子邮件：liulongchao#im.ac.cn(#替换成@)

通讯地址：北京市朝阳区北辰西路1号院3号

邮编：100101

研究方向

1. 以双特异性抗体，肿瘤疫苗等治疗手段为基础，开发肿瘤免疫治疗新策略

2. 以单细胞分辨率绘制T细胞免疫识别-免疫耐受图谱，探索免疫治疗新靶点

研究内容及意义

1. 探索肿瘤免疫治疗新策略

尽管以靶向PD-(L)1和CTLA-4为代表的免疫治疗在临床中取得了可喜的进展，但病人的总体响应率仍然较低。同时，治疗引起的副作用也限制了其广泛应用。研究认为，T细胞的浸润程度和肿瘤免疫微环境的情况都是影响免疫治疗效果的重要因素。因此，靶向肿瘤组织递送适当的免疫调节分子有望提升免疫治疗的效果。课题组聚焦于研究T细胞在肿瘤微环境中的调控机理，并通过重组蛋白技术研发靶向肿瘤组织的双特异性抗体、细胞因子以及肿瘤疫苗等治疗策略。          

2. 探索免疫治疗新靶点

T细胞在抗肿瘤免疫反应中发挥着至关重要的作用。在高度异质性的肿瘤免疫微环境中，多种细胞和分子共同参与了T细胞功能的调控。特别是在肿瘤恶性化以及免疫治疗的过程中，往往伴随着T细胞亚群的动态变化以及功能的转变。随着多组学测序技术的发展，以单细胞分辨率绘制T细胞免疫识别-免疫耐受图谱，有助于阐明T细胞免疫耐受的机理，发现免疫治疗的关键靶点，开发出新一代免疫治疗策略。

2007.09-2011.06      吉林大学 理学学士

2011.09-2016.07      中国科学院大学 理学博士

2017.02-2022.11      美国德州大学西南医学中心 博士后

2023.01-至今          中国科学院微生物研究所 研究员，课题组长

代表性论文成果

1.Wang X,Liu L*, Yue T, Sun Z, Bae J, Tseng K, Zhang A, Qian J* and Yang-Xin Fu*. Targeting tumor microenvironment with antibody-guided IL-2 pro-cytokine promotes and rejuvenates dysfunctional CD8+ T cells.Signal Transduction and Targeted Therapy2023, doi:10.1038/s41392-023-01463-y.

2.Liu L*and Chen J. Therapeutic antibodies for precise cancer immunotherapy: current and future perspectives.Medical Review2023, doi:10.1515/mr-2022-0033.

3. Bae J^#,Liu L^#, Moore C#, Hsu E, Zhang A, Ren Z, et al. IL-2 delivery by engineered mesenchymal stem cells re-invigorates CD8(+) T cells to overcome immunotherapy resistance in cancer.Nat Cell Biol2022;24:1754-1765.

4.Liu L^#, Chen J^#, Zhang H#, Ye J, Moore C, Lu C, et al. Concurrent delivery of immune checkpoint blockade modulates T cell dynamics to enhance neoantigen vaccine-generated antitumor immunity.Nat Cancer2022;3:437-452.

5.Liu L, Chen J, Bae J, Li H, Sun Z, Moore C, et al. Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells.Nat Biomed Eng2021;5:1261-1273.

6. Zhang H^#,Liu L^#, Zhang J, Chen J, Ye J, Shukla S, et al. Investigation of Antigen-Specific T-Cell Receptor Clusters in Human Cancers.Clin Cancer Res2020;26:1359-1371.

7. Liu X^#,Liu L^#, Ren Z, Yang K, Xu H, Luan Y, et al. Dual Targeting of Innate and Adaptive Checkpoints on Tumor Cells Limits Immune Evasion.Cell Rep2018;24:2101-2111.

8. Zhu D^#,Liu L^#, Yang D, Fu S, Bian Y, Sun Z, et al. Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination.J Immunol2016;196:3079-3087.

9. Yang D^#,Liu L^#, Zhu D, Peng H, Su L, Fu YX, et al. A mouse model for HBV immunotolerance and immunotherapy.Cell Mol Immunol2014;11:71-78.

共同作者论文

1. Moore C, Bae J,Liu L, Li H, Fu YX, Qiao J. Exogenous signaling repairs defective T cell signaling inside the tumor microenvironment for better immunity.JCI Insight2022;7.

2. Li H, Liu Z,Liu L, Zhang H, Han C, Girard L, et al. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1(+) CD8 T cells.Cell Rep Med2022;3:100554.

3. Lu C, Guan J, Lu S, Jin Q, Rousseau B, Lu T, Stephens D, Zhang H, Zhu J, Yang M, Ren Z, Liang Y, Liu Z, Han C,Liu L, Cao X, Zhang A, Qiao J, Batten K, Chen M, Castrillon DH, Wang T, Li B, Diaz LA, Jr., Li GM, Fu YX. DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity.Cancer Cell2021;39:96-108 e106.

4. Han C, Godfrey V, Liu Z, Han Y,Liu L, Peng H, et al. The AIM2 and NLRP3 inflammasomes trigger IL-1-mediated antitumor effects during radiation.Sci Immunol2021;6.

5. Deng S, Sun Z, Qiao J, Liang Y,Liu L, Dong C, et al. Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3-CD8+ T cells.JCI Insight2020;5.

6. Liu Z, Han C, Dong C, Shen A, Hsu E, Ren Z, Lu C,Liu L, Zhang A, Timmerman C, Pu Y, Wang Y, Chen M, Qiao J, Fu YX. Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity.Sci Immunol2019;4.

7. Yang K, Liang Y, Sun Z,Liu L, Liao J, Xu H, et al. T cell-derived lymphotoxin limits Th1 response during HSV-1 infection.Sci Rep2018;8:17727.

8. Bian Y, Zhang Z, Sun Z, Zhao J, Zhu D, Wang Y, Fu S, Guo J,Liu L, Su L, Wang FS, Fu YX, Peng H. Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice.Hepatology2017;66:1067-1082.

研究中代表性图片

图1：双特异性抗体PD-L1xCD3介导的抗肿瘤免疫反应（Nature Biomedical Engineering, 2021）