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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 4. (a) Quantitative analysis for ABHD12 in sEVs from HNSCC cell lines (SCC25 and HN6). (b) Quantitative analysis for ABHD12 in macrophages. (c) Flow cytometry analysis for percentage of M2 macrophages (CD163+CD206+) in coculture system (25μg sEVs, 50μg sEVs and 75μg sEVs); (d-h) The 50μg sEVs (sEVsNC, sEVsABHD12-KD, sEVsABHD12-OE and sEVsRAB21-KD) derived from SCC7 were injected into tail vein. After 24 h, flow cytometry analysis for CD8+ T cells, Tregs (Foxp3+) and CD4+ T cells. (d) Percentage of CD8 T cells; (e) the PD-1 level of CD8 T cells; (f) Percentage of CD4 T cells; (g) The PD-1 level of CD4 T cells; (h) Percentage of Treg cells.
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.
