Associate ProfessorMD, PhD, FRCP(C)
Sunnybrook Health Sciences Centre
2075 Bayview Avenue, S-Wing, Room S1 16
Toronto, Ontario M4N 3M5
Phone: (416) 480-6100 x2510 or 416-480-5504
Email Dr. David Spaner
Cancer Immunometabolism and Immunotherapy
Immunotherapy mediated by T cells that can recognize and kill tumor cells has the potential to cure many forms of cancer. However, the intrinsic immunosuppressive natures of cancer cells and their microenvironments compromise proper functioning of tumor-reactive T cells and constitute a critical barrier that must be overcome for T cell immunotherapy to achieve its therapeutic potential.
Cancer cells develop unique metabolic strategies to fuel their growth and survival under harsh environmental conditions. Our laboratory is investigating the hypothesis that such metabolic strategies are coupled directly to immunosuppressive gene programs. A deeper understanding of these interrelationships is expected to result in new methods to increase the immunogenicity of cancer cells, i.e. their ability to stimulate and be killed by tumor-reactive T cells, by manipulating their metabolism.
The major model that is used in the lab is the common human leukemia, Chronic Lymphocytic Leukemia (CLL). This cancer has unique advantages for the study of human immunotherapy because it allows unparalleled access to primary tumor cells for experimental purposes. Moreover, CLL cells are thought to be transformed regulatory B cells (Bregs) and are consequently highly immunosuppressive. Clinically relevant methods that can increase the immunogenic capabilities of CLL cells should be readily applicable to less immunosuppressive cancers. Lessons learned by studying CLL cells are evaluated in models of other cancers, particularly breast cancer and melanoma.
We have shown that Toll-like Receptor (TLR)-7 agonists can increase the immunogenicity of CLL cells in vitro and cause regression of leukemic deposits in the skin but that internal tumor microenvironments are hard-wired to resist these therapeutic effects. Recently, we found that aberrant glucose metabolism in the CLL microenvironment results in glycosylation of intracellular signaling molecules and corruption of responses to immunomodulators such as TLR agonists and type 1 interferons. In addition, we found that immunosuppressive leukemic cells are highly dependent on fatty acid oxidation. This metabolic strategy is mediated by nuclear receptors, particularly the Peroxisome Proliferator Activated Receptor (PPAR) family members PPARα and PPARβ/δ. Current projects in the lab are to understand in more detail how these nuclear receptors mediate the immunosuppressive phenotypes of cancer cells by using genetic manipulation of cell lines, primary tumor cells, and mouse models. In addition, we are developing glycosylation inhibitors and PPAR antagonists as clinical strategies to improve the therapeutic efficacy of cancer immunotherapy.
For further information, please go to http://sunnybrook.ca/team/member.asp?t=13&m=162&page=172
List of Key Publications:Link to Pubmed Publications
Newell, M.K., Haughn,L., Maroun, C. and M.H. Julius . Nature 347:286, 1990. Death of Mature T Cells by Separate Ligation of CD4 and the T Cell Receptor for Antigen.
Tung S, Shi Y, Wong K, Zhu F, Gorczynski R, Laister RC, Minden M, Blechert AK, Genzel Y, Reichl U, Spaner DE. PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia. Blood 122:969-80, 2013.
Tomic J, Lichty B, Spaner DE. Aberrant interferon-signaling is associated with aggressive chronic lymphocytic leukemia. Blood 117:2668-80, 2011.
Shi Y, Tomic J, Wen F, Shaha S, Bahlo A, Harrison R, Dennis J, Williams R, Gross B, Walker S, Zuccolo J, Deans J, Hart GW, Spaner D. Aberrant O-GlcNAcylation characterizes CLL. Leukemia 24:1588-98, 2010.