Thesis Format
Monograph
Degree
Master of Science
Program
Pathology and Laboratory Medicine
Supervisor
Maleki, Saman
Abstract
CD8+ T-cells play a critical role in anti-tumour immunity, and cytokines IL-12 and IL-27 can modulate their phenotype and function. Tumour-specific CD8+ tumour-infiltrating lymphocytes (TILs) can be identified based on the surface expression of CD39, while CD8+ TILs that recognize cancer unrelated antigens do not. It is currently unclear how and why tumour-specific CD8+ T-cells uniquely express CD39. We hypothesize that IL-12 and IL-27 upregulate CD39 expression on CD8+ T-cells and improve effector activity of CD39+CD8+ T-cells, compared to their CD39- counterparts. Using in vitro stimulation assays, we identified that CD8+ T-cells upregulate CD39 in the presence of IL-12 and IL-27. Moreover, CD39+CD8+ T-cells produced higher levels of effector molecules, such as IFN-γ, than CD39- counterparts. Inhibiting IL-12 activity, in vivo, reduced CD39+CD8+ TIL frequency compared to controls, without changing the overall CD8+ TIL frequency. Our findings shed light on some underlying mechanisms of CD39 upregulation by CD8+ T-cells.
Summary for Lay Audience
Strong immune responses are capable of mediating tumour regression. Immunotherapy is a modern form of cancer treatment that makes use of a patient’s own immune system to kill cancerous cells. However, many cancer patients do not benefit from immunotherapy. To improve these therapies, further research is required to understand how immune responses can be altered. Most of the current immunotherapies work by boosting the action of killer T-cells that can specifically recognize cancerous cells. Tumour-specific killer T-cells are important because they can target and destroy cancerous cells while leaving healthy cells alone. Scientists can identify tumour-specific killer T-cells by a certain molecule found on the cell surface called CD39. More research is needed to understand why and how CD39 ends up on the surface of these cells, since this could be used to improve immunotherapies. We hypothesized that two other molecules, called IL-12 and IL-27, make killer T-cell express CD39. This is because IL-12 and IL-27 are known to boost anti-tumour immune responses and improve the function of killer T-cells. In this study, we activated killer T-cells in test tubes with or without IL-12 and IL-27. In the presence of IL-12 or IL-27, T-cells had more CD39 on their surface than the control conditions. In addition, the presence of both IL-12 and IL-27 in the test tube caused the highest amount of CD39. Next, we blocked IL-12 activity in animals that had tumours and found less CD39+ killer T-cells within those tumours. This supported our previous findings. Finally, we compared the function of CD39- and CD39+ killer T-cells. We found that CD39+ killer T-cells had stronger immunological activities than CD39- cells. These results help us better understand what factors influence tumour-specific killer T-cells. Our study shows that IL-12 and IL-27 can increase the level of CD39 on the surface of killer T-cells. Also, CD39+ killer T-cells can produce strong immune responses in test tubes. This research will contribute to the growing knowledge of tumour-specific killer T-cells and may help inform scientists when designing future immunotherapies.
Recommended Citation
Gerhardt, Lara E., "The Role of IL-12 and IL-27 in Modulating CD39 Expression on CD8⁺ T-cells and Their Effector Function" (2022). Electronic Thesis and Dissertation Repository. 9006.
https://ir.lib.uwo.ca/etd/9006