Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells.
Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells.
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REIC/DKK-3蛋白在癌细胞中PD-L1调节中的新型细胞外作用。
DOI：
10.1007/s00109-023-02292-w
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发表时间：
2023-04
影响因子：
4.7
通讯作者：
Sakaguchi, Masakiyo
中科院分区：
文献类型：
--
作者：
Gohara, Yuma;Tomonobu, Nahoko;Kinoshita, Rie;Futami, Junichiro;Audebert, Lena;Chen, Youyi;Komalasari, Ni Luh Gede Yoni;Jiang, Fan;Yoshizawa, Chikako;Murata, Hitoshi;Yamamoto, Ken-ichi;Watanabe, Masami;Kumon, Hiromi;Sakaguchi, Masakiyo
腺病毒-ReIC/DKK-3表达载体(Ad-ReIC)因其潜在的肿瘤猝灭作用而成为众多临床研究的焦点。REIC/DKK-3基因的抑癌机制依赖于对癌症产生直接和间接影响的多条途径。这种直接作用是由REIC/DKK-3介导的内质网应激引起的肿瘤选择性细胞凋亡所触发的，间接作用可分为两类：(1)由腺病毒感染的肿瘤相关成纤维细胞诱导产生IL-7，IL-7是T细胞和NK细胞的重要激活剂；(2)由分泌的REIC/DKK-3蛋白促进单核细胞树突状细胞极化。这些独特的功能使Ad-reic能够以抗癌疫苗的方式发挥有效和选择性的防癌效果。然而，REIC/DKK-3蛋白如何发挥抗癌免疫作用的问题仍有待回答。在此，我们报道了细胞外REIC/DKK-3的一种新功能，即通过调节癌细胞表面的PD-L1来调节免疫检查点。首先，我们鉴定了REIC/DKK-3与膜蛋白C5aR、CXCR2、CXCR6和CMTM6的新相互作用。这些蛋白质都起到稳定细胞表面PD-L1的作用。由于CMTM6在癌细胞中的优势表达，我们接下来将重点放在CMTM6上，观察到REIC/DKK-3与CMTM6竞争PD-L1，从而将PD-L1从与CMTM6的络合中解放出来。释放的PD-L1立即进行内吞作用介导的降解。这些结果不仅加深了我们对胞外Reic/DKK-3蛋白的生理性质的理解，而且也加深了我们对Adreic介导的抗癌作用的理解。·REIC/DKK-3蛋白通过加速PD-L1降解有效抑制乳腺癌进展。·通过主要与CMTM6结合，保持了癌细胞膜上PD-L1的高度稳定性。·REIC/DKK-3蛋白与CMTM6竞争结合释放PD-L1，导致PD-L1降解。网上版载有补充材料，可在10.1007/s00109-023-02292-w查阅。
The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3—namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects. • REIC/Dkk-3 protein effectively suppresses breast cancer progression through an acceleration of PD-L1 degradation. • PD-L1 stability on the cancer cell membrane is kept high by binding with mainly CMTM6. • Competitive binding of REIC/Dkk-3 protein with CMTM6 liberates PD-L1, leading to PD-L1 degradation. The online version contains supplementary material available at 10.1007/s00109-023-02292-w.
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影响因子：
3.7
作者：
Shien K;Tanaka N;Watanabe M;Soh J;Sakaguchi M;Matsuo K;Yamamoto H;Furukawa M;Asano H;Tsukuda K;Nasu Y;Huh NH;Miyoshi S;Kumon H;Toyooka S
通讯作者：
Toyooka S
影响因子：
2.6
作者：
Sakaguchi, Masakiyo;Watanabe, Masami;Kinoshita, Rie;Kaku, Haruki;Ueki, Hideo;Futami, Junichiro;Murata, Hitoshi;Inoue, Yusuke;Li, Shun-Ai;Huang, Peng;Putranto, Endy Widya;Ruma, I. Made Winarsa;Nasu, Yasutomo;Kumon, Hiromi;Huh, Nam-ho
通讯作者：
Huh, Nam-ho
影响因子：
78.5
作者：
Sahai, Erik;Astsaturov, Igor;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
6.4
作者：
通讯作者：
--
DOI：
10.4137/cmo.s23252
发表时间：
2015
期刊：
Clinical Medicine Insights. Oncology
影响因子：
--
作者：
Kumon H;Sasaki K;Ariyoshi Y;Sadahira T;Ebara S;Hiraki T;Kanazawa S;Yanai H;Watanabe M;Nasu Y
通讯作者：
Nasu Y