Lu, Ligong, Jun Jiang, Meixiao Zhan, Hui Zhang, Qian-Ting Wang, Sheng-Nan Sun, Xiao-Kai Guo, et al. “Targeting Tumor-Associated Antigens in Hepatocellular Carcinoma for Immunotherapy: Past Pitfalls and Future Strategies.” Hepatology 73, no. 2 (February 2021): 821–32. https://doi.org/10.1002/hep.31502.
You-Wen He, MD, PhD
We study T cell biology in health and disease. Our current study is divided into two parts. Part I is to investigate T lymphocyte-mediated anti-caner immunity. We have found that host complement inhibits the cytokine IL-10 production in CD8+ tumor infiltrating lymphocytes through complement receptors C3aR and C5aR. Complement-deficient animals are resistant to tumor development in a T cell- and IL-10-dependent manner. CD8+ tumor infiltrating T cells express IL-10 when complement signaling is disabled. We found that tumor infiltrating lymphocytes from human cancers expanded with IL-2 plus IL-10 are potent tumor killers. Complement-mediated inhibition on antitumor immunity is independent of the PD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ tumor infiltrating lymphocytes represent a novel class of immune checkpoints that needs to be targeted for tumor immunotherapy. Our current effort is to enhance cancer immunotherapy through several strategies. First, we investigate a combined blockade of complement signaling and anti-PD-1 to enhance the antitumor efficacy; second, we are studying the antitumor efficacy of a targeted delivery of IL-10 to antitumor CD8+ T cells by using anti-PD1-IL-10 or anti-CTLA-4-IL-10 fusion proteins; third, we are studying the tumor killing efficacy of addition of IL-10 in the expansion protocol of tumor infiltrating lymphocytes for adaptive cellular therapy.
Part II is to investigate the intracellular process termed autophagy in T lymphocyte function. Autophagy is a highly conserved self-digestion pathway that plays essential roles in maintaining the homeostasis of organelles, degrading long-lived proteins and recycling amino acids under starvation conditions. We have found that autophagy related molecules are expressed in T lymphocytes and autophagy occurs inside T lymphocytes. We have generated autophagy-deficient T lymphocytes in multiple genetic models and investigated the roles of autophagy in T lymphocytes. We found that autophagy plays a critical role in T lymphocyte function. Our current effort is to elucidate the molecular pathways by which TCR signal induces autophagy and the impact of autophagy on intracellular organelle homeostasis in dividing T cells.
Education and Training
- Senior Fellow, Immunology, University of Washington, 1996 - 2000
- Ph.D., University of Miami, 1996
- M.D., Fourth Military Medical University (China), 1986
Selected Grants and Awards
- Basic Immunology Training Program
- A Novel Immune Modulating Antibody for the Treatment of Lung Cancer
- Medical Scientist Training Program
- The impact of genetic diversity among Akkermansia strains on the effectivenes of immune checkpoint inhibitors in cancer immunotherapies
- T cell receptor-activated autophagy as a regulator of T cell effector responses
- Organization and Function of Cellular Structure
- Quinolizidines as Novel HIV-1 Entry Inhibitors
- Regulation of T cell exhaustion by microRNA-720
- Training Program in Inflammatory and Immunological Diseases
- Validation of a microRNA signature for the prediction, diagnosis and prognosis of acute graft-versus-host disease
- Plasma microRNAs as non-invasive biomarker for acute graft-versus-host diseases
- Autophagy in T lymphocyte function
- BcI-2 family in T lymphocyte homeostasis
- Regulation of thymocyte maturation and mature T lymphocyte homeostasis by c-FLIP
- The effects of Nlrp12 and IL-1b in inflammatory disorders
- A novel pathway regulating cytokine production and asthma development
- Function of thymic epithelial cells in T lymphocyte maturation
- Extracellular Matrix Protein in Innate Immunity
- Pattern Recognition Molecule Mindin As Adjuvant
- Orphan Nuclear Receptor in Thymocyte Differentiation
Lu, Ligong, Hui Zhang, Meixiao Zhan, Jun Jiang, Hua Yin, Danielle J. Dauphars, Shi-You Li, Yong Li, and You-Wen He. “Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?” Sci China Life Sci 63, no. 12 (December 2020): 1833–49. https://doi.org/10.1007/s11427-020-1859-y.
Csepregi, Janka Zsófia, Anita Orosz, Erik Zajta, Orsolya Kása, Tamás Németh, Edina Simon, Szabina Fodor, et al. “Myeloid-Specific Deletion of Mcl-1 Yields Severely Neutropenic Mice That Survive and Breed in Homozygous Form.” J Immunol 201, no. 12 (December 15, 2018): 3793–3803. https://doi.org/10.4049/jimmunol.1701803.
Jia, W., I. McLeod, M. X. He, and Y. W. He. “The Role of Macroautophagy in T Cells.” In Immunology: Immunotoxicology, Immunopathology, and Immunotherapy, 1:23–33, 2018. https://doi.org/10.1016/B978-0-12-809819-6.00003-4.
Csepregi, J. Z., E. Zajta, K. Csonka, Y. -. W. He, A. Gacser, and A. Mocsai. “The Mcl-1 Delta Myelo mice are highly susceptible to microbial infections.” In European Journal of Clinical Investigation, 47:145–145. WILEY, 2017.
Wang, Yu, Sheng-Nan Sun, Qing Liu, Yang-Yang Yu, Jian Guo, Kun Wang, Bao-Cai Xing, et al. “Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.” Cancer Discov 6, no. 9 (September 2016): 1022–35. https://doi.org/10.1158/2159-8290.CD-15-1412.