ERK5 modulates IL-6 secretion and contributes to tumor-induced immune suppression

Abstract

Tumors exhibit a variety of strategies to dampen antitumor immune responses. With an aim to identify factors that are secreted from tumor cells, we performed an unbiased mass spectrometry-based secretome analysis in lung cancer cells. Interleukin-6 (IL-6) has been identified as a prominent factor secreted by tumor cells and cancer-associated fibroblasts isolated from cancer patients. Incubation of dendritic cell (DC) cultures with tumor cell supernatants inhibited the production of IL-12p70 in DCs but not the surface expression of other activation markers which is reversed by treatment with IL-6 antibody. Defects in IL-12p70 production in the DCs inhibited the differentiation of Th1 but not Th2 and Th17 cells from naïve CD4+ T cells. We also demonstrate that the classical mitogen-activated protein kinase, ERK5/MAPK7, is required for IL-6 production in tumor cells. Inhibition of ERK5 activity or depletion of ERK5 prevented IL-6 production in tumor cells, which could be exploited for enhancing antitumor immune responses.

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

“…Moreover, ERK5 ablation in malignant mesothelioma cells is accompanied by a significant reduction in tumor size as a result of the downregulation of critical angiogenesis-related (IL-8, VEGF) and proinflammatory (RANTES/CCL5, MCP-1/CCL2) cytokines [ 81 ]. Furthermore, recent studies on LC cells identified ERK5 as a key regulator of IL-6 secretion, which in turn determined the production of IL-12p70 by dendritic cells (DCs) and impaired the differentiation of Th1 cells [ 164 ].…”

TLR7 agonists modulate the activation of human conjunctival epithelial cells induced by IL-1β via the ERK1/2 signaling pathway

“…NF-κB signaling or the MAPK signaling pathway are typically responsible for controlling the production of in ammatory factors [31,32]. As a result, we were able to identify the protein levels and phosphorylation levels of the pathways major players, ERK1/2, p38, JNK, and p65.…”

Development of in vitro laboratory models of the tumor immune microenvironment to evaluate quality parameters and specific efficacy of the dendritic cell vaccine

“…В литературе также имеются противоречивые данные о том, что IL-6 в опухолевом микроокружении способствует как дифференцировке иммуносупрессивных опухоль-ассоциированных макрофагов, миелоидных супрессорных клеток [23,24], толерогенных ДК [25], так и дифференцировке, активации и пролиферации Т-лимфоцитов [24,26]. IL-10 описан как мощный иммуносупрессивный фактор, способствующий привлечению в опухоль Treg и подавлению NK-клеток [27,28], а также дифференцировке макрофагов в М2 [29,30] и приобретению ДК толерогенного фенотипа [25,31].…”