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The key role of IL-6-arginase cascade for inducing dendritic cell-dependent CD4(+) T cell dysfunction in
Yoshinori Narita1, Hidemitsu Kitamura, Daiko Wakita
1Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
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 N(ω)-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 N(ω)-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.
Insights
Interleukin-6 (IL-6) suppresses anti-tumor immunity by increasing arginase activity in dendritic cells (DCs), reducing MHC class II. Blocking IL-6 signaling restores T cell responses and inhibits tumor growth.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Medicine
Background:
- Tumor-induced immune dysfunction hinders effective cancer treatment.
- Interleukin-6 (IL-6) is implicated as a key factor in cancer cachexia and immune suppression.
- Understanding the mechanisms of immune evasion in tumors is crucial for developing novel therapies.
Purpose of the Study:
- To investigate the role of IL-6 in suppressing CD4(+) T cell-mediated immunity during tumor progression.
- To elucidate the impact of IL-6 on dendritic cell (DC) function, specifically arginase activity and MHC class II expression.
- To evaluate the therapeutic potential of blocking the IL-6 signaling pathway in vivo.
Main Methods:
- Assessed CD4(+) T cell responses and tumor growth in tumor-bearing mice.
- Administered anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb) and arginase-1 inhibitors.
- Analyzed arginase activity, arginase-1 mRNA, and MHC class II expression on dendritic cells (DCs) in vitro and in vivo.
- Measured serum IL-6 levels and DC characteristics in tumor-infiltrating cells.
Main Results:
- IL-6 suppressed CD4(+) T cell immunity by downregulating MHC class II on DCs via enhanced arginase activity.
- Administration of anti-IL-6R mAb restored T cell responses and inhibited tumor growth.
- IL-6 upregulated arginase-1 expression and activity in DCs.
- Arginase-1 inhibition with N(ω)-hydroxy-L-arginine prevented MHC class II reduction on DCs and enhanced anti-tumor immunity.
Conclusions:
- IL-6-induced arginase activation in DCs leads to reduced MHC class II expression, causing immune dysfunction in tumor-bearing hosts.
- Targeting the IL-6-arginase pathway represents a promising strategy to restore anti-tumor immunity.
- Blockade of IL-6 signaling offers a potential therapeutic approach for overcoming immune suppression in cancer.
