Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity

Abstract

Accompanied by the growing clinical applications of immunotherapy in the treatment of cancer patients, development of novel therapeutic approaches to reverse the immune-suppressive environment in cancer patients is eagerly anticipated, because the success of cancer immunotherapy is currently limited by immune-suppressive effects in tumor-bearing hosts. Interleukin (IL)-6, a pleotropic proinflammatory cytokine, participates in tumor cell-autonomous processes that are required for their survival and growth, and is therefore known as a poor prognostic factor in cancer patients. In addition, an emerging role of IL-6 in modulating multiple functions of immune cells including T cells, dendritic cells, and macrophages is responsible for the dysfunction of innate and adaptive immunity against tumors. Therefore, the IL-6-targeting approach is of value as a promising strategy for desensitization and prevention of immune-suppressive effects, and should be an effective treatment when combined with current immunotherapies. The aim of the present review is to discuss the immune-suppressive aspects of IL-6, notably with modification of T-cell functions in cancer patients, and their relationship to anti-tumor immune responses and cancer immunotherapy.

Keywords: T cell; Th1; cancer immunotherapy; immune suppression; interleukin-6.

Figure 1

Interleukin (IL)‐6 signaling forms a pro‐tumorigenic immune‐suppressive network. Tumor cells supply and receive the IL‐6 signal in an autocrine way. Tumor‐initiated qualitative changes in immune cells have been further implicated in IL‐6 production from myeloid‐derived suppressor cells (MDSC), dendritic cells (DC), and fibroblasts/endothelial cells. IL‐6 inhibits the maturation of DC, and promotes the generation of immune‐suppressive alternatively activated (M2) macrophages and regulatory DC. These compromise the activation/priming of tumor‐specific T cells. In addition, IL‐6 dampens Th1 differentiation of CD4⁺ T cells, which decreases their ability to help CD8⁺ T cells and DC, resulting in impaired adaptive immune responses against the tumors. IL‐6 stimulates the production of immune‐suppressive factors such as IL‐10, prostaglandin E2 (PGE ₂), and vascular endothelial growth factor (VEGF) by myeloid cells. These IL‐6‐mediated events not only weaken the innate immune responses, but also promote tumor vascularization by acting cooperatively with tumor‐associated fibroblasts/endothelial cells. Through mutual interactions among these cells, IL‐6 exacerbates the immune‐suppressive network in tumor‐bearing hosts. IFN, interferon

Figure 2

Increased baseline risk of interleukin (IL) signaling is a potential cause of dysfunction in T‐cell immunity and decreases the responsiveness to cancer immunotherapies. When young individuals are given immunotherapy, both CD4⁺ and CD8⁺ T cells are likely to differentiate into T helper cells (Th1) and CTL to eliminate the tumor. However, IL‐6 is systemically increased with aging in humans (upper right panel) and in mice.32 The excessive level of IL‐6 attenuates Th1 differentiation through c‐Maf up‐regulation and IL‐4/IL‐21 production. Impaired Th1 differentiation results in inefficient anti‐tumor activities of CTL (right panel). Therefore, increased baseline of IL‐6 level in elderly or obese individuals is one of the possible risk factors for lower responsiveness to cancer immunotherapies and subsequent poor clinical outcomes (left panel). CXCR3, chemokine (C‐X‐C motif) receptor 3; IFN, interferon

Figure 3

Transcription factor c‐Maf dampens the anti‐tumor activity of CD4⁺ T cells. (A) Using ovalbumin (OVA) as a surrogate tumor‐associated (neo‐) antigen (TAA) and OVA‐specific OT‐II T‐cell receptor (TCR) transgenic CD4⁺ T cells, cell‐intrinsic effects of c‐Maf on anti‐tumor activity of CD4⁺ T cells were evaluated. OT‐II T cells from wild‐type or Ofl (loss‐of‐function mutant of c‐Maf)32 background were transferred into young or aged C57BL/6 mice, and the mice were immunized by the transfer of OVA peptide‐pulsed dendritic cells. (B) Six days after in vivo priming of donor OT‐II cells, their differentiation status was evaluated by intracellular cytokine staining of interferon (IFN)‐γ and interleukin (IL)‐17A. IFN‐γ‐producing Th1 cells were reduced in WT but not in Ofl/+ T cells in aged mice (left). IL‐17A expression was not affected by c‐Maf activity (right). (C) To examine the role of c‐Maf activity on anti‐tumor effects, these immunized mice were inoculated with luciferase/OVA‐expressing melanoma (MO4) i.v. and the progression of pulmonary metastatic tumor was monitored by in vivo imaging of luciferase activity.32 Tumor progression was significantly inhibited by Ofl/+ CD4⁺ T cells in aged mice, suggesting that c‐Maf is a key factor for the impaired anti‐tumor immune‐response in aged mice. Multiple comparisons were carried out by one‐way anova followed by Tukey–Kramer post‐hoc tests. n = 4‐10. **P < .01, ***P < .001. NS, not significant

Figure 4

Combination of cancer immunotherapies with interleukin (IL)‐6 blockade. There are several immunotherapies, such as vaccination with tumor‐associated (neo‐) antigens (TAA) plus adjuvant or with TAA‐loaded dendritic cells (DC), immune‐checkpoint blockade targeting programmed cell death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1), and the adoptive transfer of tumor‐specific T cells. These immunotherapies quantitatively increase the numbers of tumor‐specific T cells in cancer patients. However, the immune‐suppressive environments alter or undermine the quality of activated T cells (increase in IL‐4/10‐producing cells, dysfunctional CTL). IL‐6 blockade is one of the promising approaches to improve the quality of T cells. Therefore, combinations of current immunotherapies with IL‐6 blockade need to be conducted for inducing more efficient anti‐tumor immune responses