Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer

SIMPLE SUMMARY: Lipids (fatty substances) and cytokines are molecules that affect how the immune response works. The measurement of the amounts of lipids and cytokines in blood might give clues about how prostate cancers grow or respond to treatment. This study looked at the blood levels of lipids and cytokines in men with advanced prostate cancer that was growing despite standard treatment (metastatic castration-resistant prostate cancer, mCRPC). We found that certain lipids were consistently associated with poorer clinical outcome, while cytokines were not. The levels of a type of lipid (ceramide) were associated with some cytokines. This lipid is known to activate the immune system and is associated with poor outcomes in mCRPC. A change in lipid profiles was associated with better response to treatment. Overall, our findings suggest that blood lipids might be more informative than cytokines, might influence the immune response, and might help predict treatment response. ABSTRACT: Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.