Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells

被引:4
作者
Gohara, Yuma [1 ]
Tomonobu, Nahoko [1 ]
Kinoshita, Rie [1 ]
Futami, Junichiro [2 ]
Audebert, Lena [1 ,5 ]
Chen, Youyi [1 ,6 ]
Komalasari, Ni Luh Gede Yoni [1 ,7 ]
Jiang, Fan [1 ]
Yoshizawa, Chikako [1 ]
Murata, Hitoshi [1 ]
Yamamoto, Ken-ichi [1 ]
Watanabe, Masami [3 ]
Kumon, Hiromi [4 ]
Sakaguchi, Masakiyo [1 ]
机构
[1] Okayama Univ, Dept Cell Biol Dent & Pharmaceut Sci, Grad Sch Med, 2-5-1 Shikata-Cho, Kita Ku, Okayama, Okayama 7008558, Japan
[2] Okayama Univ, Dept Interdisciplinary Sci & Engn Hlth Syst, Okayama, Japan
[3] Okayama Univ, Dept Urol Dent & Pharmaceut Sci, Grad Sch Med, Okayama, Japan
[4] Okayama Univ, Innovat Ctr Okayama Nanobio Targeted Therapy, Okayama, Japan
[5] Sorbonne Univ, Coll Doctoral, F-75005 Paris, France
[6] Harbin Med Univ, Dept Gen Surg & Biobank Gen Surg, Affiliated Hosp 4, Harbin 150001, Peoples R China
[7] Udayana Univ, Fac Med, Denpasar, Bali, Indonesia
来源
JOURNAL OF MOLECULAR MEDICINE-JMM | 2023年 / 101卷 / 04期
关键词
Breast cancer; REIC; Dkk-3; PD-L1; Immune checkpoint; Cancer therapy; LOCALIZED PROSTATE-CANCER; REIC GENE-THERAPY; MONOCYTE DIFFERENTIATION; DOWN-REGULATION; TUMOR-GROWTH; OVEREXPRESSION; EXPRESSION; ACTIVATION; APOPTOSIS; VECTOR;
D O I
10.1007/s00109-023-02292-w
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.Key messages center dot REIC/Dkk-3 protein effectively suppresses breast cancer progression through an acceleration of PD-L1 degradation.center dot PD-L1 stability on the cancer cell membrane is kept high by binding with mainly CMTM6.center dot Competitive binding of REIC/Dkk-3 protein with CMTM6 liberates PD-L1, leading to PD-L1 degradation.
引用
收藏
页码:431 / 447
页数:17
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