Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Medical and Molecular Genetics.
J Clin Invest. 2021 May 17;131(10). doi: 10.1172/JCI146832.
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.
肿瘤细胞免疫逃逸的主要机制之一是抗原性丧失，这是由于缺乏免疫原性肿瘤抗原以及抗原加工机制失调所致。在从草药中筛选增强 T 细胞介导的细胞毒性的小分子化合物的筛选中，我们发现了苍术内酯 I（ATT-I），它可显著促进人和小鼠结直肠癌（CRC）细胞的肿瘤抗原呈递，从而增强 CD8+T 细胞的细胞毒性反应。使用多重定量质谱的细胞热转移分析（CETSA）鉴定了蛋白酶体 26S 亚基非 ATP 酶 4（PSMD4），它是免疫蛋白酶体复合物的一个基本组成部分，是 ATT-I 的主要靶蛋白。ATT-I 与 PSMD4 的结合增强了免疫蛋白酶体的抗原加工活性，导致癌细胞上 MHC-I 介导的抗原呈递增强。在同种异体小鼠 CRC 模型和人源性 CRC 类器官模型中，ATT-I 治疗促进了 CD8+T 细胞的细胞毒性，从而显著增强了免疫检查点阻断治疗的疗效。总之，我们在这里表明，用 ATT-I 靶向免疫蛋白酶体的功能可促进肿瘤抗原呈递并增强 T 细胞的细胞毒性，从而提高肿瘤对免疫疗法的反应。
