Myeloid-derived suppressor cells-new and exciting players in lung cancer

Abstract

Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.

Keywords: Anticancer; Immunosuppression; Lung cancer; MDSCs.

Fig. 1

Immunosuppressive functions of MDSCs in the tumor microenvironment. DCs: dendritic cells; TAM: tumor-associated macrophage; ER: endoplasmic reticulum; Arg-1: arginase 1; iNOS: inducible nitric oxide synthase; HIF-1α: hypoxia-inducible factor-1α; STAT3: signal transducer and activator of transcription 3; VEGF: vascular endothelial growth factor; TF: tissue factor. In the tumor microenvironment, MDSCs are exposed to hypoxic conditions. This leads to an increase in HIF-1α-mediated elevation of Arg1 and iNOS and upregulation of inhibitory PD-L1 on the MDSC surface, all of which can suppress T cell immune activity. It also produces IL-10 and TGF-β, etc., which attract Treg cells to the tumor site and enhance their immunosuppressive functions, while suppressing the functions of B cells, NK cells, and DCs. Adenosine from CD39-high/CD73-high MDSCs is a further major NK suppressive factor. Much of the STAT3 activity in MDSCs is greatly reduced due to the effects of hypoxia. This leads to the rapid differentiation of M-MDSCs to TAMs. PMN-MDSCs die quickly due to ER stress. Factors released by dying cells can promote immunosuppressive mechanisms. At the same time, MDSCs can promote tumor angiogenesis and metastasis by producing VEGF, MMPs, and exosomes. Tumor tissue-derived exosomes can also affect MDSC recruitment and immunosuppression