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dc.contributor.authorXu, Hanchen
dc.contributor.authorVan der Jeught, Kevin
dc.contributor.authorZhou, Zhuolong
dc.contributor.authorZhang, Lu
dc.contributor.authorYu, Tao
dc.contributor.authorSun, Yifan
dc.contributor.authorLi, Yujing
dc.contributor.authorWan, Changlin
dc.contributor.authorSo, Ka Man
dc.contributor.authorLiu, Degang
dc.contributor.authorFrieden, Michael
dc.contributor.authorFang, Yuanzhang
dc.contributor.authorMosley, Amber L
dc.contributor.authorHe, Xiaoming
dc.contributor.authorZhang, Xinna
dc.contributor.authorSandusky, George E
dc.contributor.authorLiu, Yunlong
dc.contributor.authorMeroueh, Samy O
dc.contributor.authorZhang, Chi
dc.contributor.authorWijeratne, Aruna B
dc.contributor.authorHuang, Cheng
dc.contributor.authorJi, Guang
dc.contributor.authorLu, Xiongbin
dc.date.accessioned2021-06-07T14:02:17Z
dc.date.available2021-06-07T14:02:17Z
dc.date.issued2021-05
dc.identifier.urihttp://hdl.handle.net/10713/15921
dc.description.abstractOne 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.en_US
dc.description.urihttps://doi.org/10.1172/JCI146832en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJournal of Clinical Investigationen_US
dc.subjectAntigen processingen_US
dc.subjectCancer immunotherapyen_US
dc.subjectColorectal canceren_US
dc.subjectImmunologyen_US
dc.subjectOncologyen_US
dc.titleAtractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation.en_US
dc.typeArticleen_US
dc.identifier.doi10.1172/JCI146832
dc.identifier.pmid33830945
dc.source.journaltitleThe Journal of clinical investigation
dc.source.volume131
dc.source.issue10
dc.identifier.eissn1558-8238
dc.source.countryUnited States
dc.identifier.journalThe Journal of clinical investigation


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