Enhancing Anti-Tumour Cytotoxic Lymphocyte Responses by Targeting FES in Antigen Presenting Cells
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Authors
Dmytryk, Natasha
Date
Type
thesis
Language
eng
Keyword
Immunotherapy , Tumour microenvironment , Innate immunity , Adaptive immunity , Tumour immune evasion , Antigen presenting cells , Inflammatory cytokines , FES tyrosine kinase
Alternative Title
Abstract
The non-receptor tyrosine kinase FES has been implicated in the suppression of inflammatory signaling pathways in antigen-presenting cells (APCs) proposing that it might be dampening APC production of inflammatory cytokines in the tumour niche. These cytokines constitute the third and final signal of cytotoxic lymphocyte (CTL) activation – one of the main anti-tumour immune cells. This thesis explores the effect of FES disruption in APCs, specifically, its effect on inflammatory signaling, Signal 3 cytokine production and CTL priming. Immunoblotting analysis of the inflammatory signaling cascade showed that lipopolysaccharide (LPS)-stimulated fes-/- bone marrow-derived macrophages (BMDMs) display enhanced induction of inflammatory signaling cascades, compared to fes+/+ BMDMs. Additionally, RNA sequencing analysis revealed that in response to LPS-stimulation, certain key Signal 3 cytokine mRNA transcripts show a trend of higher production by fes-/- BMDMs. While a multiplexed cytokine detection assay did not reveal differences between fes+/+ and fes-/- BMDM secretion of these cytokines into culture media, flow cytometry analysis revealed a significantly higher frequency of fes-/- BMDMs with detectable IL-12 levels at the cell surface. This provides a possible rationale for fes-/- BMDMs being more effective at presenting antigen to and activating CTLs; and this was experimentally observed using co-cultures of OT-I CTLs with BMDMs presenting chicken ovalbumin (OVA). Collectively, these observations suggest that the apparent immunosuppressive function of FES makes it an actionable target for improving the efficacy of immunotherapies aimed at enhancing anti-cancer adaptive immune responses, including immune checkpoint inhibitors.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.