The effect of prostaglandin E2 on natural killer cell activity

Tumour cells and other cell types within the tumour micro-environment (TME) are immunosuppressive and enable cancer cells to avoid immunemediated destruction. One mechanism of immune escape is through secretion of immunosuppressive molecules. Several cancers are known to secrete prostaglandin E2 (PGE2) in the TME, which inhibits various functions of immune cells, via engagement with the PGE2 receptors EP1-4.
This study aims to explore the inhibitory effect of PGE2 on NK cell cytotoxicity against cancer cells. Peripheral blood mononuclear cells (PBMCs) were isolated using density gradient centrifugation. Whole PBMCs or isolated NK cells were pre-treated with synthetic PGE2 and activated with cytokines (IL-2, IL-15, IL-12 and IL18) and reovirus. Flow cytometry was used to assess NK cell activation and degranulation. RT-PCR was used to detect the expression of EP1-4. Enzyme linked immunosorbent assays were used to detect IFN-γ in cell supernatants. Western Blot were used to detect the inhibitory effect of PGE2 on pSTAT pathways in IL-15 mediated-NK cells.
NK cells expressed the EP2 and EP4 PGE2 receptors. PGE2 inhibited cytokine-mediated increases in NK cell CD69 expression, IFN-γ secretion and degranulation against tumour cell targets. Moreover, the use of EP2 and EP4 receptor inhibitors restored NK cytotoxicity to some extent, revealing that PGE2 exerts its inhibitory effects on NK cells at least in part through the EP2 and EP4 receptors. Importantly, PGE2 suppresses IL-15-mediated activation of the pSTAT5 pathway in NK cells, revealing that PGE2 blocks a fundamental pathway in NK cell activation.
Tumour cells can change and maintain the conditions for their own survival and development through autocrine and paracrine secretion, thereby promoting the growth and development of tumours. PGE1 alcohol can induce cancer cells to produce PGE2 and inhibit NK cell cytotoxicity through EP3 and EP4. When tumour cells were co-cultured with TAMs and MSCs in 3D model, spheroids produced large amounts of PGE2.