Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation.
Author
Xu, HanchenVan 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
Date
2021-05Journal
Journal of Clinical InvestigationPublisher
American Society for Clinical InvestigationType
Article
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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.Identifier to cite or link to this item
http://hdl.handle.net/10713/15921ae974a485f413a2113503eed53cd6c53
10.1172/JCI146832
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