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    Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation.

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    Author
    Xu, Hanchen
    Van der Jeught, Kevin
    Zhou, Zhuolong
    Zhang, Lu
    Yu, Tao
    Sun, Yifan
    Li, Yujing
    Wan, Changlin
    So, Ka Man
    Liu, Degang
    Frieden, Michael
    Fang, Yuanzhang
    Mosley, Amber L
    He, Xiaoming
    Zhang, Xinna
    Sandusky, George E
    Liu, Yunlong
    Meroueh, Samy O
    Zhang, Chi
    Wijeratne, Aruna B
    Huang, Cheng
    Ji, Guang
    Lu, Xiongbin
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    Date
    2021-05
    Journal
    Journal of Clinical Investigation
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/JCI146832
    Abstract
    One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy. © 2021, American Society for Clinical Investigation.
    Keyword
    Antigen processing
    Cancer immunotherapy
    Colorectal cancer
    Immunology
    Oncology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/15921
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI146832
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