725 W Lombard St. Baltimore, MD 21202
Education and Training
Peking Union Medical College, Beijing, China, MD, 1987.
Yale University, Immunobiology, New Haven, CT, PhD, 1994.
Resident, Internal Medicine, PUMC Hospital, Beijing, China, 1987-1989.
Resident, Pathology, New York University Medical Center, NY, 1994-1998.
Our lab's research interests are tumor immunology, cancer biology and signal transduction in hematopoietic stem cells (HSC) and cancer stem cells.
My PhD training was in protein kinases, signal transduction and cell cycle regulation. I did my post-doctoral research training in tumor immunology studying the mechanism of tumor immune evasion. I started working on the function of B7-CTLA4 interaction over 20 years ago. Together with Dr. Yang Liu’s lab, we made significant progress in making a human CTLA-4 knock in mouse strain that became an important animal model in studying adverse effects of combination antibody therapy. With optimal timing of administration of combinational immunotherapy of Ipilimumab (FDA approved anti-human CTLA4 antibody drug) and anti-PD-1, this mouse model faithfully recapitulates majority of immunotherapy related adverse events (irAE) reported in clinical trials. We generated several anti-human CTLA4 antibodies that separated the anti-tumor effect with autoimmune adverse effect. Using this model, we questioned the conventional dogma of anti-CTLA-4 antibody as a checkpoint blocking for its anti-tumor function. We raised the possibility that tumor infiltrating Treg depletion in tumor microenvironment through ADCC or ADCP is the major contributing mechanism for anti-CTLA4 antibodies.
One of our major efforts is in study TSC-mTOR signaling in rejuvenation of hematopoietic stem cells (HSC) and immunity. Using genetically modified mice with conditionally deletion of hematopoietic lineage cells, my laboratory demonstrated that mTOR inhibition is critical to maintain hematopoietic stem cell quiescence. Activation of mTOR in HSC increased mitochondrial biogenesis and elevated levels of reactive oxygen species (ROS). The most important finding with immediate clinical implication is that short-term rapamycin treatment greatly enhanced the efficacy of influenza vaccination in aged mice. We have also independently come to the conclusion that inhibition of mTOR activity can prolong the life span. This work, reported in Science Signaling, has gained wide recognition. It has been selected as one of the significant research findings in 2009. My laboratory made discovery in elucidation of an mTORC1-Mdm2-Drasha axis for microRNA biogenesis. Most excitingly, through analyzing bone marrow cells that deleted Raptor, we identified a novel cell population that we named as Innate Myelolymphoblastoid Effector Cells (IMLEC), which generated upon inactivation of mTOR signaling that have unique high expression of PD-L1 and TLRs.
Tumor Immunology, Immunotherapy, Hematopoietic Stem Cells, Signal Transduction in Hematopoiesis, Cancer Stem Cells. T Cell Development, Immune Tolerance.
1. Du X, Liu M, Su J, Zhang P, Tang F, Ye P, Devenport M, Wang X, Zhang Y, Liu Y, Zheng P. 2018. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res 2018, Feb 20. doi: 10.1038/s41422-018-0012-z. [Epub ahead of print], PMID: 29463898.
2. Du X, Tang F, Liu M, Su J, Zhang Y, Wu W, Devenport M, Lazarski CA, Zhang P, Wang X, Ye P, Wang CY, Hwang E, Zhu T, Xu T, Zheng P, Liu Y. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res2018. Feb 22. doi: 10.1038/s41422-018-0011-0. [Epub ahead of print], PMID: 29472691.
3. Tang F, Zhang P, Ye P, Lazarski CA, Wu Q, Bergin IL, Bender TP, Hall M, Cui Y, Zhang LG, Jiang TJ, Liu Y, Zheng P. 2017. A Population of Innate Myelolymphoblastoid Effector Cell Expanded by Inactivation of mTOR Complex 1 in Mice. Elife. 2017 Dec 5;6. pii: e32497. doi: 10.7554/eLife.32497.
4. Ye P, Liu Y, Chen C, Tang F, Wu Q, Wang X, Liu CG, Liu X, Liu R, Liu Y, Zheng P. 2015. An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation. Mol Cell 19:708-20.
5. Chen C, Liu Y, Liu Y, Zheng P. 2009. mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells. Science Signaling 2:ra75.