Scientist profiles S-Z

Education:

• MD, 1984, University of Alberta, Canada
• PhD, 1995, medical biophysics, University of Toronto, Canada

Appointments and Affiliations:

• Senior scientist, Biological Sciences, Odette Cancer Research Program, Sunnybrook Research Institute
• Associate professor, department of medical biophysics, University of Toronto

Research Foci:

• Cancer immunology
• Signal transduction
• Vaccines
• Toll-like receptors
• Cytokines
• Metabolism

Research Summary:

Cancer Immunometabolism and Immunotherapy

Immunotherapy mediated by T cells that can recognize and kill tumour 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 tumour-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 tumour-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 tumour 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 tumour 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 PPARa and PPARb/d. 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 tumour 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.

Selected Publications:

See current publications list at PubMed.

1. Spaner DE, Luo Y, Wang G, Gallagher J, Tsui H, Shi Y. Janus kinases restrain chronic lymphocytic leukemia cells in patients on ibrutinib: Results of a phase II trial. Cancer Med. 2021 Dec;10(24):8789-8798. doi: 10.1002/cam4.4378. Epub 2021 Nov 17. PMID: 34791813; PMCID: PMC8683523.
2. Spaner DE. O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers. Front Immunol. 2021 Nov 18;12:772304. doi: 10.3389/fimmu.2021.772304. PMID: 34868034; PMCID: PMC8639227.
3. Xia M, Luo TY, Shi Y, Wang G, Tsui H, Harari D, Spaner DE. Effect of Ibrutinib on the IFN Response of Chronic Lymphocytic Leukemia Cells. J Immunol. 2020 Nov 15;205(10):2629-2639. doi: 10.4049/jimmunol.2000478. Epub 2020 Oct 16. PMID: 33067379.
4. Shi Y, Wang G, Muhowski EM, McCaw L, Wang C, Bjarnason G, Woyach JA, Spaner

Related News and Stories:

• Higher-Dose Immunoglobulin Replacement Therapy in Chronic Lymphocytic Leukemia (September, 2018)
• Six world-class research teams to investigate overcoming therapeutic resistance in high fatality cancers (October, 2017):
• SRI scientists top the national average in successful CIHR project grants: Over a dozen projects approved (June 2, 2017)

Related Links:

• U of T profile, department of medical biophysics