Li Zhang
MD, PhD
Dr. Zhang obtained her M.D. from Anhui Medical University, in China and Ph.D. from the Leiden University in the Netherlands. She joined the faculty of Medicine at the University of Toronto in 1994 and is a Professor in the Departments of Laboratory Medicine and Pathobiology and Immunology at the University of Toronto. She holds a Maria H. Bacardi Chair in Transplantation. Professor Zhang’s research, supported by the Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, the US Leukemia & Lymphoma Society and National Institutes of Health, has been focused on understanding the cellular and molecular mechanisms involved in immunity and tolerance and its applications in various diseases, including graft rejection, graft versus host disease and cancer.
Research Synopsis
Our research is focused on developing novel immunotherapies to treat cancers, graft-vs.-host disease and transplant rejection, and understanding the mechanisms involved.
Our laboratory's research is focused on the following two major areas:
1) Developing novel adoptive T cell therapy for the treatment of leukemia and lung cancer.
Human CD3+CD4-CD8-CD56- T cells, termed double negative (DN) T cells, compose a small population of peripheral T cells. Interestingly, DN T cells could also prevent death of recipients inoculated with a lethal dose of lymphoma. The function of human DN T cells was not known due to the low frequency of DN T cells and lack of specific markers to positively select them. Recently, we have developed a novel protocol by which therapeutic quality and quantity of human DN T cells can be obtained from peripheral blood of healthy donors by ex vivo expansion. More importantly, we have demonstrated that these ex vivo propagated human DN T cells have potent anti-tumour function both in vitro and in patient-derived xenograft models. DN T cells effectively target lung cancer and primary leukemic cells, including those that are resistant to chemotherapy while spare normal blood and bone marrow cells. Unlike conventional T cells, infusion of DN T cells does not cause tissue damage or graft-versus-host disease, supporting the safety of clinical use of DN T cells. Based on these findings, phase I clinical trials using DN T cells to treat patients with acute myeloid leukemia who are at high risk of disease recurrence has been started. As cryopreserved DN T cells from one healthy donor can target leukemic cells obtained from different patients in a non-HLA-restricted manner, it is possible to develop DN T cells as “off-the-shelf” living drugs. We are currently investigating the mechanisms by which these human DN T cells selectively recognize and kill cancer cells but not normal cells and tissues, and exploring the possibility of using DN T cells either alone or in combination with other therapies to eliminate cancer cells and prevent disease recurrence.
2) Dissecting cellular and molecular mechanisms involved in immunity and tolerance and their relevance in diseases.
The ability to induce unresponsiveness to our own tissue and transplanted cells, tissues and organ grafts while retaining immune responses towards viruses and malignant cells has been a dream of immunologists and clinicians for many years. To achieve this goal requires a deep understanding of the cellular and molecular mechanisms that control and regulate immune responses. Our lab has been studying the mechanisms by which immune regulatory T cells, particularly NK-CD3+ CD4 and CD8 double negative regulatory T cells (DN Tregs) in controlling immune related diseases. Our previous studies have demonstrated that treatment with murine DN Tregs resulted in suppressing allograft rejection, inhibiting autoimmune diseases and attenuating graft vs. host disease. We have now developed a novel protocol for large scale expansion of human DN Tregs. Another research focus of our laboratory is to understand the cellular and molecular mechanisms governing tolerance and immunity and to translate obtained knowledge into novel immunotherapies to treat graft-vs-host disease and transplant rejection using ex vivo expanded human DN Tregs.
Recent Publications
Z.X. Zhang, L.M. Yang, K.J. Young, B. DuTemple and L. Zhang: Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nature Medicine, 6:782-789, 2000.
K.J. Young, L.M. Yang, M.J. Phillips and L. Zhang: Donor-lymphocyte infusion induces tolerance by activating systemic and graft-infiltrating double negative T regulatory cells. Blood, 100: 3408-3414, 2002.
M. Ford, K.J. Young, Z.X. Zhang, P. Ohashi and L. Zhang: The immune regulatory function of lpr DN T cells in vitro and in vivo. J. Exp. Med. 196: 261-267, 2002.
K.J. Young, L.S. Kay, M. J. Philips and L. Zhang: Anti-tumor activity mediated by double negative T cells. Cancer Res., 63: 8014-8021, 2003.
M. S. Ford, K.J. Young, J. Gao, B. Joe, and L. Zhang: In vivo trogocytosis as a mechanism of DN Treg cell-mediated antigen-specific suppression. Cutting Edge J. Immunol. 181: 2271-2275, 2008.
P. Dokouhaki, M. Han, B. Joe, M. Li, M.R. Johnston, M. S. Tsao, and L. Zhang: Adoptive Immunotherapy of Cancer using Ex vivo Expanded Human γδ T Cells: A new approach. Cancer Letters, 297(1):126-36, 2010.
S. Merims, X. J. Li, B. Joe, P. Dokouhaki, M. Han, Z. Y. Wang, R.W. Childs, V. Gupta, M. D. Minden and L. Zhang: Anti leukemia effect of ex vivo expanded DNT cells from AML patients: a potential novel autologous T cell adoptive immunotherapy. Leukemia, 25:1415-1422, 2011.
J. F. Gao, M. S. Ford McIntyre, J. Diao, S. C. Juvet, X.J. Li, R. B. Vanama, T. W. Mak, M. S. Cattral and L. Zhang: Regulation of Antigen Expressing Dendritic Cells by Double Negative Regulatory T cells. Eur. J. Immunol., 41: 2699-2708, 2011.
S. C. Juvet, M. Han, E. Y. Kim, C. Jeon, O. Adeyi, F. Zhao R. Vanama, B. Joe, and L. Zhang: Autocrine IFNγ controls the regulatory function of lymphoproliferative double negative T cells. PLoS One, 7 (10) e47732, online Oct. 15, 2012.
Lo Yan, L. S. Singh, L. Zhang*, and Yan Xu*. Role of OGR1 in myeloid-derived cells in prostate cancer. Oncogene, December 10, 2012 doi:10,1038/onc.2012.566. (*co-corresponding authors).
S.C. Juvet, C. W. Thomson, E. Y. Kim, B. Joe and L. Zhang: FcRγ promotes T cell apoptosis in Fas-deficient mice. J. Autoimmunity, 42: 80-93, 2013.
P. Dokouhaki, N.W. Schuh, B. Joe, C. A.D. Allen, S. Der, M. S. Tsao and L. Zhang: NKG2D regulates production of soluble TRAIL by ex vivo-expanded human gamma delta T cells. Eur. J. Immunol., DOI:10.1002/dji.201243150, published online Oct. 1, 2013.
S.C. Juvet, C.W. Thomson, E.Y. Kim, M. Han and L. Zhang: FcRγ controls the Fas-dependent regulatory function of lymphoproliferative double negative T cells. PLoS One, 8:(6), e65253, 2013.
J.F. Gao, M. S. Ford McIntyre, C.A. D’Souza, and L. Zhang: Pretransplant infusion of donor B cells enhances donor-specific skin allograft survival. PLoS One, 8:10, e77761, 2013.
A. Kowalczyk, C.A. D’Souza and L. Zhang: Cell-extrinsic CTLA4-mediated regulation of dendritic cell maturation depends on STAT3. Eur. J. Immunol, DOI: 10.1002/eji.201343601, 2013.