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Master
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Identification of the intrinsic factors responsible for the increased T-cell mediated anti-tumour responses in Arginase 2 knock-out mice

ContributorsConti, Mark
Master program titleMaîtrise universitaire (Master) en Biologie, orientation libre
Defense date2018
Abstract

Cancer is regarded by many as the “disease of the century” and, as such, sparked more and more interest among researchers. Solid evidence indicates that one of the core features of cancer as a whole, is the ability of cancer cells to modify their metabolism and reshape their environment. As our understanding of cancer metabolism and how it affects surrounding cells grows, more and more metabolic pathways are regarded as potential targets in immunotherapies as they affect components of the immune system. L-arginine metabolism is one of these pathways; arginine is a semi-essential amino acid, it is metabolised by two competing enzymes, arginase and nitric oxide synthase and is involved in numerous cellular function including immunity. For decades, evidence has been gathered regarding the involvement of arginase 1 (Arg1), one of the two isoforms of arginase, in the impairment of immune functions. Moreover, both isoenzymes have been identified as upregulated in numerous cancer types. While most of the focus has been put on Arg1 due to it being the most expressed of the two in numerous immune cells, arginase 2 (Arg2) has been found to be a key player of T-cell function and the T-cell anti-tumour response. Here, we show, using flow cytometry, qPCR and ELISA, that deleting Arg2 in mice has an effect on multiple aspects of T-cell biology. We observed differences in activation kinetics in both CD8+ and CD4+ T-cells indicating that Arg2-/- T-cells are activated faster than WT T-cells. Additionally, we observed that Arg2-/- CD8+ T-cells shed CD62L faster and produce more IFNγ but do not produce more perforin compared to WT CD8+ T-cells. Our results also show that, while there is no difference in proliferation in the CD8+ lineage, Arg2-/- CD4+ T-cells proliferate more and produce more IL-2 than WT CD4+ T-cells. Finally, we also unveiled a link between L-arginine concentration and the mitochondrial mass of CD8+ T-cells. Globally, the results of this work show that the deletion of Arg2 allows for a better T-cell response in line with previous observations that Arg2 acts as an immune brake in the context of T-cell mediated immune responses.

eng
Keywords
  • Arginase 2
  • Arg2
  • Immunology
  • Cancer
  • T-cells
Citation (ISO format)
CONTI, Mark. Identification of the intrinsic factors responsible for the increased T-cell mediated anti-tumour responses in Arginase 2 knock-out mice. 2018.
Main files (1)
Master thesis
accessLevelRestricted
Identifiers
  • PID : unige:106250
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