Prostaglandin E2 Impacts Multiple Stages of the Natural Killer Cell Anti-Tumour Immune Response

Abstract

Tumour immune escape is a major factor contributing to cancer progression and unresponsiveness to cancer therapies. Tumours can produce prostaglandin E2 (PGE2), an inflammatory mediator that directly acts on natural killer (NK) cells to inhibit anti-tumour immunity. However, precisely how PGE2 influences NK cell tumour-restraining functions remains unclear. Here, we report that following PGE2 treatment, human NK cells exhibited altered expression of specific activating receptors and a reduced ability to produce interferon-g, degranulate and kill cancer target cells. Using live cell imaging, we showed that in presence of PGE2, the dynamics of how NK cells interact with and kill cancer targets are also disrupted. NK cells are both slower and less likely to kill cancer target cells following conjugation, with killing delayed by over one hour in the presence of PGE2. Imaging the sequential stages of NK cell killing revealed that PGE2 impaired polarisation of the NK cell microtubule organising centre, but not the re-organisation of synaptic actin or the release of perforin itself. This was paralleled by impaired phosphorylation of ERK in PGE2-treated NK cells. Finally, transcriptional analysis uncovered that PGE2 also differentially modulated the expression of chemokine receptors by NK cells, inhibiting CXCR3 but increasing CXCR4. Consistent with this, PGE2-treated NK cells exhibited decreased migration to CXCL10 but an increased ability to migrate towards CXCL12. Together, these findings demonstrate that PGE2 affects multiple but select NK cell functions. Ultimately, understanding the mechanisms underlying how cancer cells subvert NK cells is necessary to more effectively harness the cancer-inhibitory function of NK cells in treatments.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Supervisor), Daniel Davis (Supervisor) & Santiago Zelenay (Supervisor)