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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation
Hanchen Xu, … , Guang Ji, Xiongbin Lu
Hanchen Xu, … , Guang Ji, Xiongbin Lu
Published April 8, 2021
Citation Information: J Clin Invest. 2021;131(10):e146832. https://doi.org/10.1172/JCI146832.
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Research Article Immunology Oncology Article has an altmetric score of 11

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

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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.

Authors

Hanchen Xu, Kevin Van der Jeught, Zhuolong Zhou, Lu Zhang, Tao Yu, Yifan Sun, Yujing Li, Changlin Wan, Ka Man So, Degang Liu, Michael Frieden, Yuanzhang Fang, Amber L. Mosley, Xiaoming He, Xinna Zhang, George E. Sandusky, Yunlong Liu, Samy O. Meroueh, Chi Zhang, Aruna B. Wijeratne, Cheng Huang, Guang Ji, Xiongbin Lu

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Figure 6

ATT-I enhances the immune checkpoint blockade immune responses.

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ATT-I enhances the immune checkpoint blockade immune responses.
(A–C) Ef...
(A–C) Effects of the ATT-I (daily) and anti–PD-1 (3 times/week, 5 injections in total) on tumor growth (A) and tumor volume (B) of MC38-derived tumors in the subcutaneous C57BL/6 mouse model. Error bars represent SEM (n = 10 mice per group). Data shown are 1 representative of 2 independent experiments. Statistical analysis was conducted using 2-way ANOVA (A) and 1-way ANOVA (B). Pictures of the resected tumors (C). Scale bar: 1 cm. (D and E) Effects of the ATT-I (50 mg/kg, daily) and anti–PD-1 (200 μg/mouse, 3 times/week, 5 injections in total) on tumor growth, measured via bioluminescence imaging (F) and survival (G) on the orthotopic MC38-derived tumor model (log-rank test). Each group includes 5 mice. (F) Tumor growth curves of MC38-derived tumors with or without PSMD4 knockdown and treated with anti–PD-1 only or anti–PD-1 together with ATT-I (combo). Each group includes 6 mice. Statistical analysis was conducted using 2-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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