Gregor Reid

 
Prospective Graduate Students / Postdocs

This faculty member is currently not actively recruiting graduate students or Postdoctoral Fellows, but might consider co-supervision together with another faculty member.

Associate Professor

Research Classification

Vaccine and Cancer
Immunotherapy
Immune System

Research Interests

paediatric cancer

Relevant Degree Programs

 

Research Methodology

mouse modelling of cancer
in vivo bioluminescent imaging
patient-derived xenografts

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
The influence of the immune system on acute lymphoblastic leukemia progression (2017)

The immune system has been proposed to have an impact on the etiology of B-cell ALL; however, a mechanistic explanation of this influence remains elusive. Epidemiological studies have uncovered a paradox, such that surrogates of infection exposure have consistently been associated with reduced ALL risk, while documented infections have a more variable influence, with both positive and negative risk associations being uncovered. Despite these contradictory findings, timing of infection exposure has been identified as a critical variable. A mechanistic explanation for the variable influences of infection or the importance of timing remain poorly defined. In this study, I use the Eµ-RET and E2A-PBX1 mouse models to assess how the basal and stimulated immune system is capable of influencing disease progression. My results indicate that in the absence of infection, resting IFN-γ is capable of influencing disease progression in the Eμ-RET mouse. By modulating SOCS-1 expression levels, IFN-γ restricted the IL-7-driven proliferation of leukemia-initiating cells (LICs) and caused a significant delay in disease progression. Furthermore, TLR ligand-mediated immune modulation inhibited disease progression by inducing the depletion of LICs through a mechanism that involved the direct activity of type-1 and type-2 interferon. Importantly, the relevance of this mechanism in humans was validated through the use of both human immune-effector and leukemia cells. Finally, I demonstrate that quantitative and qualitative differences in neonatal immune responses, in particular the increased capacity for IL-17A production by γδ T-cells, confer significant infection-induced protection from ALL progression in neonatal mice.Mechanistically these findings represent several firsts in the investigation of how the immune system influences B-cell ALL progression. They identify both type-1 and type-2 IFN and IL-17A as important inhibitory factors, and demonstrate the significant impact of immune modulation during the pre-leukemic phase on subsequent disease risk and progression. Furthermore, the results presented here provide a mechanistic explanation for the importance of timing in the association between infection exposure and ALL risk. Collectively, my results indicate that in addition to the educational influence suggested by the “delayed infection” hypothesis, early-life infection exposure may also have an active inhibitory impact on the progression of B-cell ALL.

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Master's Student Supervision (2010 - 2018)
Application of Saccharomyces cerevisiae to improve pediatric acute lymphoblastic leukemia outcomes (2018)

Pediatric acute lymphoblastic leukemia (ALL) is the most commonly diagnosed childhood cancer in Canada and continues to need improvements in the care patients receive. Saccharomyces cerevisiae (S. cerevisiae) is a generally nonpathogenic organism that has the potential to affect both stages of leukemia (preleukemia and leukemia) and improve ALL outcomes by acting as a drug delivery vehicle for L-ASNase and/or influence leukemogenesis by inducing early-life, antileukemic immune activity. Mild infectious exposures during infancy and childhood has consistently been shown to influence leukemogenesis. In mice, early-life infections can deplete preleukemic cells and prevent preleukemia developing into leukemia. If preleukemia develops into ALL, children undergo chemotherapy that includes the enzyme L-asparaginase (L-ASNase). ALL cells characteristically stop expressing the enzyme asparagine synthetase (AS) and rely on extracellular sources for L-ASN. L-ASNase depletes extracellular L-ASN, selectively starving ALL cells of L-ASN, and consequently inducing their apoptosis. To evaluate the efficacy of S. cerevisiae to improve L-ASNase therapy, it was first engineered to constitutively express cell-wall associated L-ASNase-II (AEY – asparaginase expressing yeast). The cell-wall association may improve ALL therapy by shielding L-ASNase from immune detection and consequently reducing the cost, toxicity, and immunogenicity of L-ASNase therapy. In vitro, AEY co-cultured with ALL cell lines can deplete L-ASN levels leading to apoptosis and inhibited cell growth in the asparagine synthetase (AS)-negative cell line RS4;11, but not the AS-positive cell lines BV173 and 697. The AEY biomass required to yield a therapeutic L-ASNase dose exceeds the current ethical limitations for further study in vivo. To determine if S. cerevisiae can activate early-life, antileukemic immune activity, S. cerevisiae was injected intraperitoneally into day-6-old Eμ-RET mice and the effect on preleukemic burden was assessed. S. cerevisiae is unable to activate the IL-17A and Natural Killer (NK) cell-dependent immune response that has been shown to deplete preleukemic cells. Additionally, both in vitro and in vivo stimulation of NK cells with IL-17A does not directly lead to their activation. Further investigation into the mechanism leading to the activation of antileukemic NK cells may uncover new immunotherapeutic approaches for ALL.

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Publications

 

Membership Status

Member of G+PS
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