Abstract
We studied the subsets of peripheral blood dendritic cells (DCs) and lipid accumulation in DCs to investigate the involvement of DCs in the decreased anticancer immunity of advanced lung cancer patients. We analyzed the population of DC subsets in peripheral blood using flow cytometry. We then determined lipid accumulation in the DCs using BODIPY 650/665, a fluorophore with an affinity for lipids. Compared with healthy controls, the number of DCs in the peripheral blood of treatment-naive cancer patients was significantly reduced. In patients with stage III + IV disease, the numbers of myeloid DCs (mDCs) and plasmacytoid DCs were also significantly reduced. Lipid accumulation in DCs evaluated based on the fluorescence intensity of BODIPY 650/665 was significantly higher in stage III + IV lung cancer patients than in the controls. In the subset analysis, the fluorescence was highest for mDCs. The intracellularly accumulated lipids were identified as triglycerides. A decreased mixed leukocyte reaction was observed in the mDCs from lung cancer patients compared with those from controls. Taken together, the results show that lung cancer patients have a notably decreased number of peripheral blood DCs and their function as antigen-presenting cells is decreased due to their high intracellular lipid accumulation. Thereby, anticancer immunity is suppressed.
Highlights
Lung cancer has a poorer prognosis compared to other cancers
Human-derived dendritic cells (DCs) are typically classified into two types, myeloid DCs and plasmacytoid DCs [7, 8]. mDCs are derived from monocytes in the peripheral blood and are differentiated by the influence of granulocyte/ macrophage colony-stimulating factor and interleukin- (IL-) 4, and they preferentially induce mature T helper 1 (Th1) cells, from naive T cells [9,10,11,12]
cytotoxic T lymphocytes (CTL), which are activated by Th1-derived cytokines, show cytotoxic activity and induce apoptosis in cancer cells, but T cell activation is reduced in cancer patients, and one possible mechanism by which this occurs is through transforming growth factor-β (TGF-β), which is released by tumor cells and suppresses the activation of Th1 cells and CTL [19, 20]
Summary
Lung cancer has a poorer prognosis compared to other cancers. The pathologic analysis of tumor immunity in patients with lung cancer is important for the advancement of immunotherapy. DCs exist in the peripheral blood in an immature state and capture and recognize specific tumor antigens They respond to inflammatory mediators such as interferonalpha and toll-like receptor (TLR) agonists, and when they mature, they present antigens to T cells and acquire the ability to activate a specific antitumor T cell response and migrate to other tissues [15, 16]. CTL, which are activated by Th1-derived cytokines, show cytotoxic activity and induce apoptosis in cancer cells, but T cell activation is reduced in cancer patients, and one possible mechanism by which this occurs is through transforming growth factor-β (TGF-β), which is released by tumor cells and suppresses the activation of Th1 cells and CTL [19, 20]. As we expect that elucidating the mechanism of lipid accumulation in DCs will lead to the development of new immunotherapy, we investigated the DC subsets and lipid accumulation in the peripheral blood of lung cancer patients to elucidate the changes in tumor immunity in lung cancer
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