Abstract
CD137 ligand-induced dendritic cells (CD137L-DCs) are a new type of dendritic cells (DCs) that induce strong cytotoxic T cell responses. Investigating the metabolic activity as a potential contributing factor for their potency, we find a significantly higher rate of glycolysis in CD137L-DCs than in granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 4 induced monocyte-derived DCs (moDCs). Using unbiased screening, Akt-mTORC1 activity was found to be significantly higher throughout the differentiation and maturation of CD137L-DCs than that of moDCs. Furthermore, this higher activity of the Akt-mTORC1 pathway is responsible for the significantly higher glycolysis rate in CD137L-DCs than in moDCs. Inhibition of Akt during maturation or inhibition of glycolysis during and after maturation resulted in suppression of inflammatory DCs, with mature CD137L-DCs being the most affected ones. mTORC1, instead, was indispensable for the differentiation of both CD137L-DCs and moDCs. In contrast to its role in supporting lipid synthesis in murine bone marrow-derived DCs (BMDCs), the higher glycolysis rate in CD137L-DCs does not lead to a higher lipid content but rather to an accumulation of succinate and serine. These data demonstrate that the increased Akt-driven glycolysis underlies the higher activity of CD137L-DCs.
Highlights
With the recent success of immune checkpoint inhibitors and chimeric antigen receptor T cells (CAR-T), tumor immunotherapy had its long-awaited breakthroughs
As the activation of Dendritic cell (DC) is accompanied by metabolic reprograming to a higher rate of glycolysis [15, 26], we compared the glycolysis rates of CD137 ligand (CD137L)-DCs and monocyte-derived DC (moDC) at baseline and under metabolic stress induced by Oligomycin
In agreement with the higher glycolysis in CD137L-DCs, Gene Set Enrichment Analysis (GSEA) showed an enrichment in enzymes involved in glycolysis in immature CD137L-DCs (Figure 1B), such as hexokinase 2 (HK2), which is a key enzyme in promoting aerobic glycolysis [27]
Summary
With the recent success of immune checkpoint inhibitors and chimeric antigen receptor T cells (CAR-T), tumor immunotherapy had its long-awaited breakthroughs. There are many cancer types where these two approaches have low to no efficacy [1,2,3]. Examples would be solid cancers that lack a cell surface tumor associated antigen (TAA) that can be targeted by CAR-T, and cancers that failed to induce an immune response [2, 3]. DCbased immunotherapy for cancer has been proven safe and to prolong survival but the clinical response and efficacy are disappointing [4]. We have discovered a new type of DCs, CD137L-DCs, which are derived from monocytes by CD137 ligand (CD137L) reverse signaling [6]. CD137L-DCs are only found in human but not in mouse because of the difference in human and mouse CD137L [7]
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