The Key Role of IL-6–Arginase Cascade for Inducing Dendritic Cell–Dependent CD4+ T Cell Dysfunction in Tumor-Bearing Mice

Abstract

Evaluation of immune dysfunction during the tumor-bearing state is a critical issue in combating cancer. In this study, we initially found that IL-6, one of the cachectic factors, suppressed CD4+ T cell–mediated immunity through downregulation of MHC class II by enhanced arginase activity of dendritic cells (DC) in tumor-bearing mice. We demonstrated that administration of Ab against IL-6R (anti–IL-6R mAb) greatly enhanced T cell responses and inhibited the growth of tumor in vivo. We also found that IL-6 upregulated the expression of arginase-1 and arginase activity of DC in vitro. Tumor-infiltrating CD11c+ DC exhibited upregulated mRNA expression of arginase-1 but reduced expression of MHC class II in parallel with the increase in serum IL-6 levels at the late stage in tumor-bearing hosts. However, the administration of anti–IL-6R mAb into tumor-bearing mice inhibited both the downmodulation of MHC class II and the upregulation of arginase-1 mRNA levels in DC. Furthermore, we noted that Nω-hydroxy-L-arginine or L-arginine, an arginase-1 inhibitor, blocked the reduction in MHC class II levels on CD11c+ DC during the tumor-bearing state. Finally, we demonstrated that the administration of Nω-hydroxy-L-arginine at the peritumor site significantly enhanced CD4+ T cell responses and inhibited tumor growth. Thus, IL-6–mediated arginase activation and the subsequent reduction in MHC class II expression on DC appeared to be critical mechanisms for inducing dysfunction of the immune system in the tumor-bearing state. Blockade of the IL-6–arginase cascade is a promising tool to overcome the dysfunction of antitumor immunity in tumor-bearing hosts.

Tocilizumab, a Proposed Therapy for the Cachexia of Interleukin6-Expressing Lung Cancer

“…Furthermore, in our previous case report, although the tumor was progressive, the cachectic condition decreased substantially [15]. However, Narita et al demonstrated that a blockade of IL-6 signaling by anti-IL6 receptor antibody exerted an antitumor effect through the down-modulation of arginase-1 activity and up-regulation of MHC class II expression on tumor-associated CD11c+ dendritic cells [43]. That is, its effect on a cachectic condition was promising, but the potential effect on tumor growth remained controversial.…”

Effects of Gastric Cancer Cells on the Differentiation of Treg Cells

“…It is well known that cell-mediated immunity in cancer hosts is suppressed by many factors (Narita et al, 2013). As an additional explanation for impaired cellmediated immunity in cancer hosts, the increased prevalence of Treg cells could be included.…”

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4+ T cells

“…In mice with tumors, IL-6 suppressed CD4 + T cell-mediated immunity through the down-regulation of MHC class II via enhanced arginase activity in DCs [16]. Administration of arginase-1 inhibitors, nor-NOHA or L-arginine, blocked the reduction of MHC class II levels in DCs during tumorigenesis.…”

“…3). We previously demonstrated that arginine was required for the gene expression of MHC class II and arginase activation induced by IL-6 caused dysfunction of DCs in a tumor-bearing mouse model [16]. The IL-6-induced activation of lysosomal proteases reduced MHC class II -dimer levels in murine DCs [13].…”