Improving cancer immunotherapy by targeting the STATe of MDSCs

Abstract

Cancer immunotherapy is a promising therapeutic avenue; however, in practice its efficacy is hampered by an immunosuppressive tumor microenvironment that consists of suppressive cell types like myeloid-derived suppressor cells (MDSCs). Eradication or reprogramming of MDSCs could therefore enhance clinical responses to immunotherapy. Here, we review clinically available drugs that target MDSCs, often through inhibition of STAT signaling, which is essential for MDSC accumulation and suppressive functions. Interestingly, several drugs used for non-cancerous indications and natural compounds similarly inhibit MDSCs by STAT inhibition, but have fewer side effects than anticancer drugs. Therefore, they show great potential for combination strategies with immunotherapy.

Keywords: Drugs; MDSCs; STAT signaling; immunotherapy; tumor microenvironment.

Figure 1.

MDSC-suppressive mechanisms target innate and adaptive arms of the immune system. (A) Myeloid-derived suppressor cells (MDSCs) can inhibit the innate immune system by TGF-β-induced inhibition of NK cell function and induction of a M2 macrophage phenotype by secretion of IL-10. (B) MDSCs deprive T cells of amino acids L-cysteine and L-arginine, which are essential for proliferation and differentiation. (C) MDSCs release reactive oxygen species, such as hydrogen peroxide (H₂O₂) and peroxynitrite (ONOO⁻). H₂O₂ causes loss of the T cell receptor (TCR)ζ-chain and peroxynitrite causes nitration and nitrosylation of chemokines like CCL2 and components of the TCR signaling complex, thereby both inhibiting T cell activation and recruitment. (D) MDSCs induce the development of regulatory T cells (Tregs) or expand existing Treg cell populations; these effects are mediated by interaction of the TCR with MHC-II and CD40 with CD40L. Furthermore, secretion of factors like IL-10 and TGF-β, and deprivation of L-arginine by MDSCs induce Treg polarization. ARG1, arginase 1; CCL2, chemokine (C–C motif) ligand 2; iNOS, inducible nitric oxide synthase; NOX2, NADPH oxidase 2; NO, nitric oxide; NK, natural killer; TGF-β, transforming growth factor-β; IL, interleukin.

Figure 2.

Induction of MDSC expansion and suppressive functions by the STAT signaling proteins. Tumor-derived factors induce signal transducers of activators of transcription (STAT) signaling, which stimulated MDSC expansion and suppressive functions. IL-4 and IL-13 induce STAT6 that regulates ARG1, leading to enhanced MDSC proliferation and survival. IL-6, GM-CSF, G-CSF and VEGF induce STAT3 signaling, which regulates ARG1, NOX2 and the expression of factors like MYC, Bcl-XL, cyclin D1, survivin and S100A9. This leads to enhanced MDSC proliferation and suppressive capacity, reduced apoptosis and inhibition of differentiation into mature cells. IFNγ and IL-1β regulate STAT1 activation, which induces iNOS and ARG1 expression by MDSCs, leading to induced proliferation and suppressive capacity. STAT5 signaling is induced by GM-CSF and inhibits the differentiation of MDSCs into mature cells through inhibition of IRF-8. IL, interleukin; IRF, interferon regulatory factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocyte-colony stimulating factor; VEGF, vascular endothelial growth factor; IFNγ, interferon-γ; JAK, Janus kinase; ARG1, arginase 1; NOX2, NADPH oxidase 2; iNOS, inducible nitric oxide synthase; Bcl-XL, B-cell lymphoma-extra-large.

Figure 3.

Mechanisms by which drugs and natural compounds inhibit MDSCs. Several drugs and natural compounds used in cancer treatment or for other indications have off-target effects that result in inhibition of myeloid-derived suppressive cells (MDSCs) through four distinct mechanisms. The off-target effects can inhibit expansion of MDSCs, inhibit their T cells suppressive capacity or induce the differentiation of MDSCs into mature APCs. Cimetidine induces the apoptosis of MDSCs. ARG1, arginase 1; iNOS, inducible nitric oxide synthase; APC, antigen-presenting cell; TCR, T cell receptor; ATRA, all-trans retinoid acid.