Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis

Abstract

Immunotherapy aiming to rescue or boost antitumor immunity is an emerging strategy for treatment of cancers. The efficacy of immunotherapy is strongly controlled by the immunological milieu of cancer patients. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cell populations with immunosuppressive functions accumulating in individuals during tumor progression. The signaling mechanisms of MDSC activation have been well studied. However, there is little known about the metabolic status of MDSCs and the physiological role of their metabolic reprogramming. In this study, we discovered that myeloid cells upregulated their glycolytic genes when encountered with tumor-derived factors. MDSCs exhibited higher glycolytic rate than their normal cell compartment did, which contributed to the accumulation of the MDSCs in tumor-bearing hosts. Upregulation of glycolysis prevented excess reactive oxygen species (ROS) production by MDSCs, which protected MDSCs from apoptosis. Most importantly, we identified the glycolytic metabolite, phosphoenolpyruvate (PEP), as a vital antioxidant agent able to prevent excess ROS production and therefore contributed to the survival of MDSCs. These findings suggest that glycolytic metabolites have important roles in the modulation of fitness of MDSCs and could be potential targets for anti-MDSC strategy. Targeting MDSCs with analogs of specific glycolytic metabolites, for example, 2-phosphoglycerate or PEP may diminish the accumulation of MDSCs and reverse the immunosuppressive milieu in tumor-bearing individuals.

Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function

“…An increased number of MDSCs has been observed in the tumor microenvironment of patients with MDS (24). These MDSCs have higher glycolytic capacity and increased mitochondrial activity (25). Thus, we examined the metabolic changes of monocytes following conditioning with MSCs.…”

Diversity and environmental adaptation of phagocytic cell metabolism

“…In vitro differentiation of BM precursors to MDSC‐like phenotype using GM‐CSF and IL‐6 enhanced glucose uptake and anaerobic glycolysis as well as glutamine utilization . Furthermore, recent studies have demonstrated that tumors increased expression of genes involved in glycolysis in both g‐ and m‐MDSC subsets . This increased glycolysis was required to promote expansion and prevent apoptosis of MDSC.…”

Resveratrol ameliorates Lewis lung carcinoma‐bearing mice development, decreases granulocytic myeloid‐derived suppressor cell accumulation and impairs its suppressive ability

“…Although G‐MDSC and M‐MDSC could both impede T cell responses, the latter was more suppressive . Except for immunosuppressive effects on cancer development, more evidence showed that MDSC could accelerate the development of cancers by inducing autophagy, reprogramming metabolic status and supporting cancer cell stemness . It remains unclear whether RSV also modulated M‐MDSC in other cancer‐bearing mice models.…”

“…40 Except for immunosuppressive effects on cancer development, more evidence showed that MDSC could accelerate the development of cancers by inducing autophagy, reprogramming metabolic status and supporting cancer cell stemness. [41][42][43] It remains unclear whether RSV also modulated M-MDSC in other cancer-bearing mice models. Therefore, in future, we will consider the influence of RSV on M-MDSC in different cancer-bearing models.…”