Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine

Abstract

Chronic immune activation and inflammation are unwanted consequences of many pathological conditions, since they could lead to tissue damage and immune exhaustion, both of which can worsen the pathological condition status. In fact, the immune system is naturally equipped with immunoregulatory cells that can limit immune activation and inflammation. However, chronic activation of downregulatory immune responses is also associated with unwanted consequences that, in turn, could lead to disease progression as seen in the case of cancer and chronic infections. Myeloid-derived suppressor cells (MDSCs) are now considered to play a pivotal role in the pathogenesis of different inflammatory pathological conditions, including different types of cancer and chronic infections. As a potent immunosuppressor cell population, MDSCs can inhibit specific and non-specific immune responses via different mechanisms that, in turn, lead to disease persistence. One such mechanism by which MDSCs can activate their immunosuppressive effects is accomplished by secreting copious amounts of immunosuppressant molecules such as interleukin-10 (IL-10). In this article, we will focus on the pathological role of MDSC expansion in chronic inflammatory conditions including cancer, sepsis/infection, autoimmunity, asthma and ageing, as well as some of the mechanisms by which MDSCs/IL-10 contribute to the disease progression in such conditions.

Keywords: PD-1/PD-L1; S100A8/A9; STAT3; dendritic cells; macrophages; natural killer cells.

Figure 1.

Mechanisms of anti-tumour immune response subversion by MDSC/IL-10. In fact, inflammation provides a signal that promotes MDSC expansion. MDSCs are primary producers of IL10 a potent antiinflammatory cytokine. In turn, MDSC-derived IL-10 and IL-10 produced by other cells could also promote the expansion of MDSC and enhance the immunosuppressive activity. IL-10 can also inhibit the production of IL-12 by dendritic cells (DCs) and macrophages (MΦ). IL-12 is essential for initiation of anti-tumour immunity by activating the maturation of natural killer (NK) cells that, in turn, produce inflammatory cytokines such as IFN-γ that further activate the maturation of professional APCs such as DCs and MΦ triggering a positive feedback loop. In addition, IL-12 can activate cytotoxic T lymphocytes (CD8⁺ T cells). NK cells and CD8⁺ T cells are essential to fight tumor cells. As such, MDSCs can inhibit antitumor immunity at least in part through production of copious amounts of IL-10, i.e. without a direct cell-to-cell contact. On the other hand, direct cross-talking between MDSCs and DCs and/or MΦ can also inhibit the maturation of DCs and blunt the production of IL-12. Rather, this direct cell contact can potentiate the production of IL-10 by MDSCs, which in turn further inhibits the production of IL-12, an essential driver of type 1 immunity ‘anti-tumour immunity’. MDSCs/IL-10 can inhibit type 1 immunity while promote the type 2 immunity that is known to promote tumour progression.