Identification of RPL15 60S Ribosomal Protein as a Novel Topotecan Target Protein That Correlates with DAMP Secretion and Antitumor Immune Activation
Identification of RPL15 60S Ribosomal Protein as a Novel Topotecan Target Protein That Correlates with DAMP Secretion and Antitumor Immune Activation
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DOI：
10.4049/jimmunol.2100963
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发表时间：
2022-06
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通讯作者：
S. Yamada;Yuichi Kitai;Takashi Tadokoro;Runa Takahashi;Haruka Shoji;Taiga Maemoto;Marie Ishiura;R. Muromoto;J. Kashiwakura;K. Ishii;K. Maenaka;T. Kawai;T. Matsuda
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作者：
S. Yamada;Yuichi Kitai;Takashi Tadokoro;Runa Takahashi;Haruka Shoji;Taiga Maemoto;Marie Ishiura;R. Muromoto;J. Kashiwakura;K. Ishii;K. Maenaka;T. Kawai;T. Matsuda
损伤相关分子模式（DAMP）有助于癌症化疗期间的抗肿瘤免疫。我们先前证明拓扑异构酶I抑制剂拓扑替康（TPT）诱导癌细胞分泌DAMP，从而激活STING介导的抗肿瘤免疫应答。然而，TPT如何诱导癌细胞中的DAMP分泌尚未阐明。在这里，我们确定了RPL 15，60 S核糖体蛋白，作为一种新的TPT靶点，并表明TPT通过与RPL 15结合抑制前核糖体亚基的形成，导致诱导DAMP介导的抗肿瘤免疫激活独立于TOP 1。TPT抑制RPL 15-RPL 4相互作用并降低RPL 4稳定性，其通过CDK 12活性恢复。在B16-F10鼠黑色素瘤模型中，RPL 15敲低诱导DAMP分泌并增加CTL群体，但减少调节性T细胞群体，这使B16-F10肿瘤对PD-1阻断敏感。我们的研究鉴定了一种新的TPT靶蛋白，并表明核糖体应激是DAMP分泌的触发因素，这有助于抗肿瘤免疫治疗。视觉摘要关键点RPL 15被确定为一种新的TPT靶标。TPT通过与RPL 15结合诱导癌细胞分泌DAMP。RPL 15抑制使B16-F10肿瘤对PD-1阻断敏感。
Damage-associated molecular patterns (DAMPs) contribute to antitumor immunity during cancer chemotherapy. We previously demonstrated that topotecan (TPT), a topoisomerase I inhibitor, induces DAMP secretion from cancer cells, which activates STING-mediated antitumor immune responses. However, how TPT induces DAMP secretion in cancer cells is yet to be elucidated. Here, we identified RPL15, a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited preribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. TPT inhibits RPL15–RPL4 interactions and decreases RPL4 stability, which is recovered by CDK12 activity. RPL15 knockdown induced DAMP secretion and increased the CTL population but decreased the regulatory T cell population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against PD-1 blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy. Visual Abstract Key Points RPL15 is identified as a novel TPT target. TPT induces DAMP secretion from cancer cells via its binding to RPL15. RPL15 inhibition sensitizes B16-F10 tumors against PD-1 blockade.