Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species

BACKGROUND: High levels of the polyunsaturated fatty acid arachidonic acid (AA) within the ovarian carcinoma (OC) microenvironment correlate with reduced relapse-free survival. Furthermore, OC progression is tied to compromised immunosurveillance, partially attributed to the impairment of natural killer (NK) cells. However, potential connections between AA and NK cell dysfunction in OC have not been studied. METHODS: We employed a combination of phosphoproteomics, transcriptional profiling and biological assays to investigate AA's impact on NK cell functions. RESULTS: AA (i) disrupts interleukin-2/15-mediated expression of pro-inflammatory genes by inhibiting STAT1-dependent signaling, (ii) hampers signaling by cytotoxicity receptors through disruption of their surface expression, (iii) diminishes phosphorylation of NKG2D-induced protein kinases, including ERK1/2, LYN, MSK1/2 and STAT1, and (iv) alters reactive oxygen species production by transcriptionally upregulating detoxification. These modifications lead to a cessation of NK cell proliferation and a reduction in cytotoxicity. CONCLUSION: Our findings highlight significant AA-induced alterations in the signaling network that regulates NK cell activity. As low expression of several NK cell receptors correlates with shorter OC patient survival, these findings suggest a functional linkage between AA, NK cell dysfunction and OC progression. High levels of the fatty acid arachidonic acid (AA) in the ovarian cancer environment are associated with shorter survival. Ovarian cancer progression is linked to weakened immune defenses, partly due to malfunctioning natural killer (NK) cells. We used various scientific methods to study how AA affects NK cell function. Our results show that AA significantly changes the signaling processes that control NK cell activity. Specifically, AA (i) disrupts the expression of pro-inflammatory genes, (ii) impairs the function of receptors that activate killing mechanisms by preventing them from appearing on the cell surface, (iii) reduces the activity of intracellular signaling proteins that are activated by these receptors and (iv) changes the production of reactive oxygen species. These changes stop NK cells from multiplying and reduce their ability to kill cancer cells, suggesting that AA contributes to NK cell dysfunction and cancer progression. eng

• Hammoud, M. K.
• Meena, C.
• Dietze, R.
• Hoffmann, N.
• Szymanski, W.
• Finkernagel, F.
• Nist, A.
• Stiewe, T.
• Graumann, J.
• von Strandmann, E. P.
• Müller, R.