NF-κB pathway orchestrates the tumor promoting role of monocytes/macrophages in human renal cell carcinoma (66.45)

Abstract Growing evidences suggests that monocyte/macrophages play crucial role in cancer progression. Even though studies in transgenic mouse tumor models have demonstrated the role of myelomonocytic cells in various aspects of tumor progression, information on the role of these cells in human cancers is limited. We investigated the role of monocytes/macrophages in the progression of a human renal Cell Carcinoma (RCC). Gene expression studies have shown that RCC associated monocytes (RCC-Mo) under basal condition exhibit a proinflammatory and protumoral phenotype characterized by high expression of genes such as TNFA, IL6, VEGFA, IL8 and MMP9. Surprisingly, when these cells were exposed to inflammatory stimuli, such as Lipid A or TNF-α, they failed to show an up- regulation of proinflammatory cytokines such as TNFA, CCL3, IL6, and IL1B. This observation correlated to the tumor-induced immunosuppression observed in the patients. Signaling studies showed that the inflammatory/protumoral phenotype of TAMs under basal condition was regulated through NF-κB pathway.Further studies demonstrated defective NF-κB signaling was responsible for the “refractory state” of this RCC-Mo to further inflammatory stimuli. In vivo studies in a human RCC mouse model validated our above findings. In conclusion these results are the first to characterize the transcriptomal and functional phenotype of tumor associated monocytes/macrophages in human cancer which suggested their tumor promoting role.