title: Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway.
abstract: Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumor-associated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAM-mediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2-dependent and 15-LOX2-independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC.
authors: Department of Urology, University of Florida, Gainesville, Florida, USA.
authors: Irina
authors: I
authors: Daurkin
authors: Evgeniy
authors: E
authors: Eruslanov
authors: Taryn
authors: T
authors: Stoffs
authors: George Q
authors: GQ
authors: Perrin
authors: Chester
authors: C
authors: Algood
authors: Scott M
authors: SM
authors: Gilbert
authors: Charles J
authors: CJ
authors: Rosser
authors: Li-Ming
authors: LM
authors: Su
authors: Johannes
authors: J
authors: Vieweg
authors: Sergei
authors: S
authors: Kusmartsev
mesh_terms: D000368:Aged; D001093:Arachidonate 15-Lipoxygenase / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000276:immunology / Q000601:surgery; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000276:immunology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000601:surgery; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D008875:Middle Aged; D009578:Nitrobenzenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C111835:CCL2 protein, human; D060908:CTLA-4 Antigen; D018932:Chemokine CCL2; D016861:Cyclooxygenase Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016859:Lipoxygenase Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016753:Interleukin-10; D009637:Masoprocol; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase