An Investigation of the Axis Connecting GPR44 and PD-1/PD-L1 in Acute Myeloid Leukemia

Open Access
- Author:
- Wunderler, Brooke
- Area of Honors:
- Immunology and Infectious Disease
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Kumble Sandeep Prabhu, Thesis Supervisor
Robert Paulson, Thesis Honors Advisor - Keywords:
- Acute Myeloid Leukemia
Programmed Cell Death
Selenium
Gpr44
PD-1/PD-L1
Cancer - Abstract:
- Acute myeloid leukemia (AML) is a blood cancer that continues to present a concern to the health of many, and the aggressive nature of this disease results in a high relapse rate among many patients after they stop treatment. Therefore, a natural and consistent method of stopping disease progression is necessary as these patients cannot endure the toxicity of chemotherapy and drug therapy for the remainder of their lives. Selenium diet supplementation appears to be a potential solution. Recent findings have shown selenium supplementation causes eicosanoid class switching to cyclopentanone prostaglandins (CyPGs) that agonize the Gpr44 G-protein coupled receptor. This receptor modulates many immune functions within the cell, but when activated, results in the downregulation of the PD-1/PD-L1 interaction commonly used for immune evasion by cancers, such as AML. With the suppression of this interaction, T cell inhibition is reduced allowing these cells to combat the cancer and thereby, resulting in better patient outcomes. This project looks to gain a more detailed understanding of the relationship between Gpr44 and the PD-1/PDL-1 interaction between T cells and AML leukemia-inducing cells (LICs). Through this project, it is demonstrated LICs lacking Gpr44 are more aggressive and induce more severe disease in mice through the upregulation of PD-L1. The upregulation of PD-L1 helps in increasing the frequency this ligand will interact with its receptor on T cells, therefore suppressing these lymphocytes and allowing the cancerous cells to evade the immune response. Additionally, this project displays Gpr44 agonism is important to limiting T cell exhaustion induced by LICs through the inhibition of PD-1 expression. This research is valuable as future AML therapies can aim to stimulate Gpr44 through selenium supplementation in order to inhibit the PD-1/PD-L1 interaction, thereby reducing cancer aggressiveness and allowing CD8+ T cells to retain their cytotoxicity.