Soluble IL-6R expressed by myeloid cells reduces tumor-specific Th1 differentation and drives tumor progression

IL-6 produced by tumor cells promotes their survival, conferring a poor prognosis in cancer patients. IL-6 also contributes to immunosuppression of CD4+ T cell-mediated antitumor effects. In this study, we focused on the impact of IL-6 trans-signaling mediated by soluble IL-6 receptors (sIL-6R) expressed in tumor-bearing hosts. Higher levels of sIL-6R circulating in blood was observed in tumor-bearing mice, whereas the systemic increase of sIL-6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL-6R even when tumor cells produced sIL-6R. Abundant sIL-6R was released by CD11b+ cells from tumor-bearing mice but not tumor-free mice. Notably, IL-6-mediated defects in Th1 differentiation, T cell helper activity for tumor-specific CD8+ T cells and downstream antitumor effects were rescued by myeloid-specific deletion of sIL-6R. Expression of the T cell transcription factor c-Maf was upregulated in CD4+ T cells primed in tumor-bearing mice in an IL-6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL-6/sIL-6R-induced Th1 suppression and defective T cell-mediated antitumor responses. In cancer patients, myeloid cell-derived sIL-6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL-6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL-6R targeting to improve the efficacy of T cell-mediated cancer immunotherapy.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2ljEzt5
via IFTTT