Wang, Y, Sun, S-N, Liu, Q, Yu, Y-Y, Guo, J, Wang, K, Xing, B-C, Zheng, Q-F, Campa, MJ, Patz, EF, Li, S-Y, and He, Y-W. "Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression." Cancer discovery 6, no. 9 (September 2016): 1022-1035.
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
- Medical Scientist Training Program
- Organization and Function of Cellular Structure
- Basic Immunology Training Program
- 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
Park, S, Buck, MD, Desai, C, Zhang, X, Loginicheva, E, Martinez, J, Freeman, ML, Saitoh, T, Akira, S, Guan, J-L, He, Y-W, Blackman, MA, Handley, SA, Levine, B, Green, DR, Reese, TA, Artyomov, MN, and Virgin, HW. "Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation." Cell host & microbe 19, no. 1 (January 2016): 91-101.
Wu, Y-J, Wu, Y-H, Mo, S-T, Hsiao, H-W, He, Y-W, and Lai, M-Z. "Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling." Journal of immunology (Baltimore, Md. : 1950) 195, no. 6 (September 2015): 2612-2623.
Wang, Y, Zhang, Z, Ji, D, Chen, G-F, Feng, X, Gong, L-L, Guo, J, Li, Z-W, Chen, C-F, Zhao, B-B, Li, Z-G, Li, Q-J, Yan, H-P, Sempowski, G, Wang, F-S, and He, Y-W. "Regulation of T cell function by microRNA-720." Scientific reports 5 (July 22, 2015): 12159-.
Kanayama, M, He, Y-W, and Shinohara, ML. "The lung is protected from spontaneous inflammation by autophagy in myeloid cells." Journal of immunology (Baltimore, Md. : 1950) 194, no. 11 (June 2015): 5465-5471.
Gehrke, N, Garcia-Bardon, D, Mann, A, Schad, A, Alt, Y, Wörns, MA, Sprinzl, MF, Zimmermann, T, Menke, J, Engstler, AJ, Bergheim, I, He, Y-W, Galle, PR, Schuchmann, M, and Schattenberg, JM. "Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors." Cell death and differentiation 22, no. 5 (May 2015): 826-837.
He, M-X, and He, Y-W. "c-FLIP protects T lymphocytes from apoptosis in the intrinsic pathway." Journal of immunology (Baltimore, Md. : 1950) 194, no. 7 (April 2015): 3444-3451.
Jia, W, He, M-X, McLeod, IX, Guo, J, Ji, D, and He, Y-W. "Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1." Autophagy 11, no. 12 (January 2015): 2335-2345.
Gao, S, Yang, C, Jiang, S, Xu, X-N, Lu, X, He, Y-W, Cheung, A, and Wang, H. "Applications of RNA interference high-throughput screening technology in cancer biology and virology." Protein & cell 5, no. 11 (November 2014): 805-815. (Review)
Chen, C-F, Feng, X, Liao, H-Y, Jin, W-J, Zhang, J, Wang, Y, Gong, L-L, Liu, J-J, Yuan, X-H, Zhao, B-B, Zhang, D, Chen, G-F, Wan, Y, Guo, J, Yan, H-P, and He, Y-W. "Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection." Scientific reports 4 (September 15, 2014): 6359-.
Wu, YH, Kuo, WC, Wu, YJ, Yang, KT, Chen, ST, Jiang, ST, Gordy, C, He, YW, and Lai, MZ. "Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation." Cell Death and Differentiation 21, no. 3 (March 1, 2014): 451-461.
Gordy, C, Liang, J, Pua, H, and He, Y-W. "c-FLIP protects eosinophils from TNF-α-mediated cell death in vivo." PloS one 9, no. 10 (January 2014): e107724-.
Koenig, A, Buskiewicz, IA, Fortner, KA, Russell, JQ, Asaoka, T, He, Y-W, Hakem, R, Eriksson, JE, and Budd, RC. "The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival." The Journal of biological chemistry 289, no. 2 (January 2014): 1183-1191.
Xiao, B, Wang, Y, Li, W, Baker, M, Guo, J, Corbet, K, Tsalik, EL, Li, Q-J, Palmer, SM, Woods, CW, Li, Z, Chao, NJ, and He, Y-W. "Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease." Blood 122, no. 19 (November 7, 2013): 3365-3375.
Panayotova-Dimitrova, D, Feoktistova, M, Ploesser, M, Kellert, B, Hupe, M, Horn, S, Makarov, R, Jensen, F, Porubsky, S, Schmieder, A, Zenclussen, A, Marx, A, Kerstan, A, Geserick, P, He, YW, and Leverkus, M. "CFLIP Regulates Skin Homeostasis and Protects against TNF-Induced Keratinocyte Apoptosis." Cell Reports 5, no. 2 (October 28, 2013): 397-408.