Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway.
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American Association for Cancer Research
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.
Medicine and Health Sciences
Aged, Arachidonate 15-Lipoxygenase, CTLA-4 Antigen, Carcinoma, Renal Cell, Cells, Cultured, Chemokine CCL2, Cyclooxygenase Inhibitors, Female, Forkhead Transcription Factors, Humans, Immune Tolerance, Interleukin-10, Kidney Neoplasms, Lipoxygenase Inhibitors, Macrophages, Male, Masoprocol, Middle Aged, Nitrobenzenes, Sulfonamides
Daurkin, Irina; Eruslanov, Evgeniy; Stoffs, Taryn; Perrin, George Q; Algood, Chester; Gilbert, Scott M; Rosser, Charles J; Su, Li-Ming; Vieweg, Johannes; and Kusmartsev, Sergei, "Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway." (2011). NSU-MD Faculty Articles. 59.