Investigating tumour-mediated immunosuppression of CD8+ T cells

Abstract

Prostaglandin E2 is a physiologically active lipid mediator. However, an upregulation of PGE2 is often seen within the tumour microenvironment of multiple cancer types, helping drive multiple aspects of tumour development. PGE2 has a versatile role in aiding tumour development and progression, including evasion of the immune system. Cytotoxic T cells play a key role in eliminating cancer cells, preventing tumour growth and development, through the specific recognition of tumour specific antigens and subsequent cytolytic function. Studies have shown 1uM PGE2 to suppress both the proliferation and effector function of naive cytotoxic T cells, preventing their cytotoxic function, in turn enabling cancer development. We aimed to determine the full extent of PGE2 induced immunosuppression of cytotoxic T cells(CTLs) in addition to the potential causative mechanism. Live cell microscopy imaging determined whether PGE2 affected the stability and maintenance of the immunological synapse, as a recently identified potential common mechanism of immune suppression. Flow cytometry analysis was used to investigate the effect of PGE2 on both proliferation and cytolytic action of CTLs. In addition, imaging-based kill assays were used to further confirm the effect of 1uM PGE2 on CTL cytolysis against Renca mCherry cells. Results showed PGE2 to have no significant effect on the stability of the immunological synapse between CTL and Renca targets. In contrast 1uM PGE2 was shown to induce significant decreases in both the proliferation and cytotoxicity of CD8+ T cells, in a non-dose dependant manner. Partial restoration of suppression was noted following the treatment of EP2 blocker TG4-155. However, the suppressive effect was completely abrogated through the addition of supplementary IL-2 into T cell culture. Overall, PGE2 was concluded to have a significant immunosuppressive effect against CTLs and therefore could potentially contribute to tumour mediated immunosuppression.

Date of Award	24 Jul 2019
Original language	English
Awarding Institution	The University of Bristol
Supervisor	David J Morgan (Supervisor) & Christoph Wuelfing (Supervisor)