Plasma Profile of Inflamatory Mediators in NHL Patients

Abstract

Both cancer and inflammation are almost invariably accompanied by lipidome dysregulation. Hence, various lipid species have been reported as candidate markers for many solid tumours 1-3 .However, neitherthe globallipidome norsub-lipidome ofinflammatory pathways in Non-Hodgkin lymphoma (NHL) has been studied. In order to fill this gap and shed light on the inflammatory pathways accompanying NHL, we designed a targeted liquid chromatography – Multiple Reaction Monitoring of bioactive lipids/lipid mediators in plasma of female patients with Diffuse Large B-cell Lymphoma (DLBCL), the most often type of NHL. We chose to quantify lipids known or hypothesized to be involved in inflammation and cancer progression along with theirmembrane precursors. In a pilot study encompassing plasma samples from 17 DLBCL patients and 21 BMI-matched controls, we analysed levels of pro-inlammatory arachidonic acid (AA)-derived oxylipins, focusing on lipoxygenase (LOX) and cytochrome P450 monooxygenase products: hydroxyeicosatetraenoic acids (HETEs) and dihydroxyeicosatrienoic acids; several AA-containing phospholipids (PLs); specificlysophospholipid subclasses; sphingomyelins (SMs), sphingosine 1-phosphate (S1P) and polyunsaturated fatty acids. Data were subjected to classical statistics and multivariate unsupervised and supervised machine learning (ML) algorithms. The DLBCL status was profoundly associated with altered S1P, SM 34:1, SM 36:1 and phosphatidylinositol PI 34:1 abundance. On the other hand, eicosanoids 12(S)-HETE, 15(S)-HETE and thromboxane B2 were major lipid species discriminating between DLBCL and healthy status, as well as lysophosphatidylinositol LPI 20:4. The correlations between lipid species varied considerably between the cancer and controls, reflecting significant changes in lipid metabolic and/or signalling pathways, particularly those within LOX pathway and cell membrane PL remodelling. We suggest S1P, SM 36:1, SM 34:1 and PI 34:1 may beviewed as lipid signatures of DLBCL. Furthermore, these four lipid species could serve asa basis for the prospective validation in larger DLBCL/NHL clinical studies. As far as we know, this is the first plasma lipid profiling in DLBCL/NHL and, as such, brings new knowledge on the metabolic basis of inflammation in this cancer. The added value of our plasma lipid profiling in DLBCL is a deeper understanding of particulate lipid dysregulations in this tumour