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Title: Regulation of the immune checkpoint PD-L1 by microRNAs
Author: Yee, Daniel
ISNI:       0000 0004 7964 6153
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2018
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MicroRNAs are evolutionary conserved non-coding RNAs that control more than 60% of human protein-coding genes at the posttranscriptional level. MicroRNAs can either mediate translational repression or mRNA degradation by complementary base-pairing to the 3'-UTR of mRNA. MicroRNAs have critical roles in the regulation of immune responses and inflammation. The expression of PD-L1 protein is found on some normal and cancer cells and contributes to suppression of T cell activity by acting as a brake on the immune response. Previously, it has been shown that posttranscriptional mechanisms regulate PD-L1 levels in cancer, it remains unknown whether such regulatory networks operate also in non-transformed cells. Here, I tested the hypothesis that expression and function of PD-L1 in stromal, vascular and cancer cells is posttranscriptionally regulated by inflammatory-driven microRNAs. I demonstrate that PD-L1 expression in human dermal lymphatic endothelial cells (HDLECs) can be induced with the treatment of pro-inflammatory cytokines IFN-y and TNF-a. The microRNA landscape in HDLECs was activated by IFN-y and TNF-a treatment including some microRNAs that have predicted binding sites on PD-L1. A highly upregulated microRNA was microRNA-155 (miR-155), a multifunctional microRNA that regulates haematopoiesis, normal immune function and mediates the inflammatory response. I determined that miR-155 can bind to the 3'-UTR of PD-L1 on two functional binding sites, and that the kinetics of PD-L1 induction is fine-tuned by inflammation-induced miR-155 in HDLECs and dermal fibroblasts. Interestingly, I found that miR-155 can also silence PD-L1 expression in renal, breast but only in a subset of lung cancer cell lines. These findings reveal that inflammatory activation induce PD-L1 expression on several different cell types presumably to avoid prolonged immune-mediated tissue damage. However, miR-155 can act in a cell type-specific manner to temporally release PD-L1 immunosuppression to regulate the balance between immune tolerance and autoimmunity.
Supervisor: Lagos, Dimitris ; Coles, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available