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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 1

ATT-I enhances the killing efficiency of CD8+ T cells against tumor cells.

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ATT-I enhances the killing efficiency of CD8+ T cells against tumor cell...
(A) A total of 594 natural small molecule compounds purified from traditional medicinal plants were tested for their toxicity on MC38 cells and T cells freshly isolated from C57BL/6 mice. Data are presented as mean of 3 independent experiments. (B) The 446 drugs with low toxicity from (A) were tested for their effects on the CD8+ T cell–mediated cytotoxicity. MC38-OVA cells expressing luciferase were cocultured with OT-I CD8+ T cells in the presence of each drug (5.0 μM) and the T cell–mediated cytotoxicity was measured by the luciferase assay. Difference (log2): (log2 [relative viability] > 1; P < 0.05). Relative viability = (tumor cell viability of treated group) / (tumor cell viability of control group). Data are presented as mean of 3 independent experiments. Statistical analysis was conducted using 1-way ANOVA. (C) Chemical structure of ATT-I. (D) The effect of ATT-I treatment on the CD8+ T cell killing of MC38-OVA cells was measured under different ratios of tumor cells versus T cells as indicated. Data are presented as mean ± SD of 3 independent experiments. Statistical analysis was conducted using 2-way ANOVA. (E) CD8+ T cell killing assays were conducted using coculture of MC38-OVA cells and OT-I CD8+ T cells pretreated with 5 μM of ATT-I (+) or vehicle control DMSO (–). Data are presented as mean ± SD of 3 independent experiments. (F) The levels of IFN-γ (left) and TNF-α (right) in the supernatants after coculture of OT-I T cells and MC38-OVA cells pretreated with ATT-I (+) or DMSO control (–) were determined by ELISA. Data are presented as mean ± SD of 3 independent experiments. Statistical analyses were conducted using 2-way ANOVA. **P < 0.01; ***P < 0.001; ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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