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posted on 2024-02-02, 08:20 authored by Kun Wu, Yan Li, Yikang Ji, Chun Liu, Xiaoning Wang, Haiyan Guo, Jianjun Zhang, Yue He Supplementary Figure 6. The upregulated S1PR1 was mediated by FoxO signaling pathway. (a) Volcano plot showing the differential expressed genes of macrophages with ABHD12-OE; (b-c) The sEVs (50 μg) derived from HNSCC cell lines were cocultured with macrophages (1 × 106) for 24 h. (b) Immunoblotting analysis for S1PR1 in macrophages cocultured with sEVs. (c) Quantitative analysis for S1PR1 in macrophages cocultured with sEVs. (d) GSEA analysis of up-stream events of FoxO regulation in macrophages with ABHD12-OE; (e-h) Quantitative analysis for AKT and FoxO1 phosphorylation in macrophages (ABHD12-OE and ABHD12-KD) following treatment with AKT inhibitor (MK-2206) or agonist (SC79). (i) The percentage of M2 macrophages after macrophages with ABHD12-KD or ABHD12-OE treated with an AKT inhibitor or agonist.
Funding
National Natural Science Foundation of China (NSFC)
Natural Science Foundation of Hunan Province (湖南省自然科学基金)
China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)
History
ARTICLE ABSTRACT
Tumor metastasis is a spatial and temporal process that starts with remodeling to generate a proper premetastatic niche in a distant tissue. Infiltration of immunosuppressive macrophages is one of the notable characteristics in the premetastatic niche, which is a fundamental requirement for primary tumor metastasis. Here, we demonstrated that small extracellular vesicles (sEV) carrying RAB21 homed to lung macrophages and interacted with integrin-β1 on macrophages. ABHD12 expression was high in lung metastatic tumors and was mostly expressed by macrophages. Head and neck squamous cell carcinoma (HNSCC)–derived sEVs carrying ABHD12-polarized macrophages toward an immunosuppressive phenotype, driving premetastatic niche formation, which facilitated lung metastasis. ABHD12 additionally upregulated S1PR1 by activating the AKT–FoxO1 pathway in macrophages, and significantly enhanced antitumor responses were observed in tumor models treated with agents targeting both S1PR1 and PD-1. Collectively, our study suggests that RAB21+ABHD12+ sEVs derived from HNSCC cells contribute to the formation of the immunosuppressive microenvironment in the premetastatic niche and are a potential therapeutic target for enhancing the antitumor efficacy of anti–PD-1 therapy.
