American Association for Cancer Research
cir-23-0221_supplement_figure_5_suppsf5.pptx (7.4 MB)

Supplement figure 5 from Tumor-Derived RAB21+ABHD12+ sEVs Drive the Premetastatic Microenvironment in the Lung

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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 5. (a) The normal saline (Control) and sEVs derived from SCC7 (50μg, sEVsNC and sEVsABHD12-KD) were injected into tail vein. After 2 h, immunofluorescence staining of ABHD12 distribution (Red) and different immune-associated cell types (Green), including macrophages (CD68+) in lung tissue. (b-d) For preparing pre-metastatic niche formation with conditional sEVs (sEVsNC, sEVsABHD12-KD, sEVsABHD12-OE and sEVsRAB21-KD) injection via tail vein every 3 day for 3 weeks, followed with tail vein injection of SCC7GFP for performing lung metastasis vivo experiment. (b) Flow cytometry analysis for Granzyme B level of CD8 T cells; (c) Flow cytometry analysis for CD44 level of CD8 T cells. (d) Flow cytometry analysis for percentage of CD4+ T cells; (e) Flow cytometry analysis for percentage of Tregs.


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)



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.

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