[HTML][HTML] M2 macrophage-derived extracellular vesicles facilitate CD8+ T cell exhaustion in hepatocellular carcinoma via the miR-21-5p/YOD1/YAP/β-catenin pathway

J Pu, Z Xu, J Nian, Q Fang, M Yang, Y Huang, W Li… - Cell death …, 2021 - nature.com
J Pu, Z Xu, J Nian, Q Fang, M Yang, Y Huang, W Li, B Ge, J Wang, H Wei
Cell death discovery, 2021nature.com
Hepatocellular carcinoma (HCC) is a common malignancy. CD8+ T cell-mediated immune
response is critical for the inhibition of HCC progression. M2 macrophages participate in
HCC progression. This study set out to investigate the effect of M2 macrophage-derived
extracellular vesicles (EVs) on CD8+ T cell exhaustion in HCC. M2 macrophage-derived
EVs were isolated and identified. The murine model of primary HCC was established
through DEN/CCl4 induction, and model mice were injected with EVs. Peripheral blood …
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy. CD8+ T cell-mediated immune response is critical for the inhibition of HCC progression. M2 macrophages participate in HCC progression. This study set out to investigate the effect of M2 macrophage-derived extracellular vesicles (EVs) on CD8+ T cell exhaustion in HCC. M2 macrophage-derived EVs were isolated and identified. The murine model of primary HCC was established through DEN/CCl4 induction, and model mice were injected with EVs. Peripheral blood mononuclear cells (PBMCs) were isolated from the mouse liver and CD8+ T cells were sorted. The expressions of immune checkpoint inhibitory receptors and effector cytokines on CD8+ T cells were detected, followed by the evaluation of CD8+ T cell proliferation and killing function. miR-21-5p expression in M2 macrophage-derived EVs was detected. The binding relationship between miR-21-5p and YOD1 was verified. The activation of the YAP/β-catenin pathway was detected. Consequently, M2 macrophage-derived EVs promoted CD8+ T cell exhaustion in HCC mice. miR-21-5p expression was upregulated in M2 macrophage-derived EVs, and EVs carried miR-21-5p into HCC tissues. miR-21-5p targeted YOD1. Inhibition of miR-21-5p or overexpression of YOD1 annulled the promoting effect of EVs on CD8+ T cell exhaustion. YOD1 inactivated the YAP/β-catenin pathway. In conclusion, M2 macrophage-derived EVs facilitated CD8+ T cell exhaustion via the miR-21-5p/YOD1/YAP/β-catenin axis. This study may confer novel insights into the immunotherapy of HCC.
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