The role of myeloid-derived suppressor cells in gastrointestinal cancer

Abstract

Gastrointestinal (GI) cancer encompasses a range of malignancies that originate in the digestive system, which together represent the most common form of cancer diagnosed worldwide. However, despite numerous advances in both diagnostics and treatment, the incidence and mortality rate of GI cancer are on the rise. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that increase in number under certain pathological conditions, such as infection and inflammation, and this expansion is of particular relevance to cancer. MDSCs are heavily involved in the regulation of the immune system and act to dampen its response to tumors, favoring the escape of tumor cells from immunosurveillance and increasing both metastasis and recurrence. Several recent studies have supported the use of MDSCs as a prognostic and predictive biomarker in patients with cancer, and potentially as a novel treatment target. In the present review, the mechanisms underlying the immunosuppressive functions of MDSCs are described, and recent researches concerning the involvement of MDSCs in the progression, prognosis, and therapies of GI cancer are reviewed. The aim of this work was to present the development of novel treatments targeting MDSCs in GI cancer in the hope of improving outcomes for patients with this condition.

Keywords: gastrointestinal cancer; myeloid-derived suppressor cells; prognosis; progression; therapy; tumor immunology.

FIGURE 1

Molecular mechanisms involved in MDSC‐mediated immunosuppression in GI cancers. In GI cancer, MDSCs accumulate and expand in the tumor microenvironment that regulated by the expression of STAT3, with TDFs, exosomes, and hypoxia‐inducible factor 1α, etc. MDSCs suppress proliferation and function of T cells and NK cells through the enzymes of ARG1 and iNOS, ROS, and expression of PD‐L1. Peroxynitrite (ONOO^–) causes the nitration of the CCL2 chemokine, which diminishes CD8⁺ T‐cell infiltration. At the same time, NO production can suppress DCs antigen presentation to CD4⁺ T cells. Additionally, the effect of ADCC function and anergy of NK cells are induced by the production of NO and the inhibition of NKG2D by TGFβ, respectively. While the expression of NKP30 ligand on MDSCs induces NK cell apoptosis, activation of TRAIL receptor could lead MDSC apoptosis conversely. MDSC‐derived IL‐10 suppresses DCs’ function, promotes M2 macrophage differentiation, and increases the number and immunosuppression of Treg. MDSC‐derived TGFβ can promote Treg expansion and immunosuppression as well. In return, MDSCs secret MMPs, exosomes, and VEGF to promote GI cancer cell proliferation and metastasis. The specific markers of CD38⁺ and SLFN4⁺ MDSCs were first reported in GI cancer. MDSCs, myeloid‐derived suppressor cells; M‐MDSC, monocytic MDSCs; G‐MDSC, granulocytic MDSCs; GI cancer, gastrointestinal cancer; TDFs, tumor derived factors; MMPs, matrix metalloproteinases; VEGFs, vascular endothelial growth factors; HIFs, hypoxia‐inducible factors; PD1, programmed cell death protein 1; PD‐L1, programmed death‐ligand 1; TCR, T‐cell receptor; CDK4, cyclin‐dependent kinase 4; ARG1, arginase I; NK cells, natural killer cells; NKP30, natural killer protein 30; iNOS, inducible nitric oxide synthase; NO, nitric oxide; ONOO‐, peroxynitrite; MHC II, major histocompatibility complex class 2; CCR2, C‐C motif chemokine receptor 2; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; MiR‐130b, microRNA 130b; SLFN4, Schlafen4; TGFβ, transforming growth factor β; NKG2D, natural killer group 2 member D; Foxp3, forkhead box P3; Treg, regulatory T‐cell; IL‐10, interleukin 10; IL‐12, interleukin 12; TAMs, tumor associated macrophages; DCs, dendritic cells; STAT3, signal transducer and activator of transcription 3