The role of obesity and insulin resistance in modulating immune cell function in cancer and liver disease

• Author / Creator

  Lee, Megan CMH

• Obesity and associated insulin resistance (IR) represent a significant global health burden, and predispose individuals to develop various diseases, including cancer and liver diseases. Heightened inflammation during obesity can on the one hand exacerbate liver inflammation, while on the other, dampen protective immune responses against tumours. However, the underlying mechanisms remain incompletely understood. My research aims to assess aspects of obesity and alterations in immune function within the context of cancer, focusing on how obesity and IR affects T cell-mediated anti-tumour responses. In addition, my research focuses on the role of Hippo signalling mediators Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ) activity in dendritic cells (DCs) in the development of IR and non-alcoholic fatty liver disease (NAFLD). In response to tension, DCs have enhanced pro-inflammatory function, but also upregulate the expression of TAZ. TAZ is involved in mechanosensing in non-immune cell types and has a homolog known as YAP, suggesting that DC mechanosensing and inflammatory function may involve YAP/TAZ signalling.

  Here, I present my findings that diet-induced obesity accelerates tumour growth, which is associated with a decrease in tumour infiltrating lymphocytes. Intratumoural T cells in obese mice also exhibit reduced effector function, but similar levels of exhaustion compared to lean mice. To determine mechanistically how T cell anti-tumour immunity is impaired during obesity, I investigated the role of insulin signalling in T cells, as we found that T cells in obese mice are insulin resistant. To assess the role of insulin signalling in T cell-mediated anti-tumour immunity, I used a mouse model with insulin receptor (INSR)-specific ablation in T cells. Genetic insulin resistance in T cells dampens antigen-specific T cell-mediated immunity, which is associated with decreased production of effector molecules, mirroring the observations in obese mice. Given that obesity imposes a similar phenotype, this supports the notion that obesity impairs T cell-mediated anti-tumour responses through inducing IR. This offers new insight into how obesity impairs immune responses in cancer, and provides implications for the potential of immunotherapies targeting immune cell metabolism against cancer.

  I also report that YAP/TAZ in DCs, which we previously observed to be important for DCs’ proinflammatory function, does not play a significant role in the pathogenesis of IR, NAFLD, and liver fibrosis in a high fat high sucrose model.
  My findings highlight the complex signals that modulate immunity during obesity, which awaits further investigation for better understanding to ultimately develop therapeutics to improve health and blunt disease.

• Subjects / Keywords

  • obesity
  • cancer
  • NAFLD
  • T cell
  • insulin resistance

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-09vj-cw55

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.