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Construction of stable membranal CMTM6-PD-L1 full-length complex to evaluate the PD-1/PD-L1-CMTM6 interaction and develop anti-tumor anti-CMTM6 nanobody

文献类型：期刊论文

作者Jia, Xiao-min2,3; Long, Yi-ru1,3; Yu, Xiao-lu1,3; Chen, Run-qiu1; Gong, Li-kun1,3,4; Geng, Yong2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2022-11-22
页码10
ISSN号1671-4083
关键词cancer immunotherapy CMTM6 CMTM6 PD-L1 complex protein interactions anti-CMTM6 nanobody
DOI10.1038/s41401-022-01020-3
通讯作者Gong, Li-kun(lkgong@simm.ac.cn) ; Geng, Yong(gengyong@simm.ac.cn)
英文摘要CKLF (chemokine-like factor)-MARVEL transmembrane domain containing protein 6 (CMTM6) is a novel regulator to maintain the stability of PD-L1. CMTM6 can colocalize and interact with PD-L1 on the recycling endosomes and cell membrane, preventing PD-L1 from lysosome-mediated degradation and proteasome-mediated degradation thus increasing the half-life of PD-L1 on the cell membrane. The difficulties in obtaining stable full-length PD-L1 and CMTM6 proteins hinder the research on their structures, function as well as related drug development. Using lauryl maltose neopentyl glycol (LMNG) as the optimized detergent and a cell membrane mimetic strategy, we assembled a stable membrane-bound full-length CMTM6-PD-L1 complex with amphipol A8-35. When the PD-1/PD-L1-CMTM6 interactions were analyzed, we found that CMTM6 greatly enhanced the binding and delayed the dissociation of PD-1/PD-L1, thus affecting immunosuppressive signaling and anti-apoptotic signaling. We then used the CMTM6-PD-L1 complex as immunogens to generate immune repertoires in camels, and identified a functional anti-CMTM6 nanobody, called 1A5. We demonstrated that the anti-CMTM6 nanobody greatly decreased T-cell immunosuppression and promoted apoptotic susceptibility of tumor cells in vitro, and mainly relied on the cytotoxic effect of CD8(+) T-cells to exert tumor growth inhibitory effects in CT26 tumor-bearing mice. In conclusion, the stable membrane-bound full-length CMTM6-PD-L1 complex has been successfully used in studying PD-1/PD-L1-CMTM6 interactions and CMTM6-targeting drug development, suggesting CMTM6 as a novel tumor immunotherapy target.
WOS关键词RECEPTOR ; PD-L1 ; CMTM6 ; IDENTIFICATION
资助项目National Natural Science Foundation of China[31670743] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040326] ; Science and Technology Commission of Shanghai Municipality[3918JC141540001] ; Joint Research Fund for Overseas, Hong Kong and Macao Scholars[81628013] ; Natural Science Foundation of Shanghai[16ZR1442900] ; National Science Foundation for Young Scholar projects[118180359901] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[CASIMM0120164013] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1606YZZ-06] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1601KF-06] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[55201631121116101] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[55201631121108000] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[5112345601] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[2015123456005] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[CASIMM0120202003]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBL GROUP
WOS记录号WOS:000886794300001
源URL[http://119.78.100.183/handle/2S10ELR8/304569]  
专题新药研究国家重点实验室
通讯作者Gong, Li-kun; Geng, Yong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Jia, Xiao-min,Long, Yi-ru,Yu, Xiao-lu,et al. Construction of stable membranal CMTM6-PD-L1 full-length complex to evaluate the PD-1/PD-L1-CMTM6 interaction and develop anti-tumor anti-CMTM6 nanobody[J]. ACTA PHARMACOLOGICA SINICA,2022:10.
APA Jia, Xiao-min,Long, Yi-ru,Yu, Xiao-lu,Chen, Run-qiu,Gong, Li-kun,&Geng, Yong.(2022).Construction of stable membranal CMTM6-PD-L1 full-length complex to evaluate the PD-1/PD-L1-CMTM6 interaction and develop anti-tumor anti-CMTM6 nanobody.ACTA PHARMACOLOGICA SINICA,10.
MLA Jia, Xiao-min,et al."Construction of stable membranal CMTM6-PD-L1 full-length complex to evaluate the PD-1/PD-L1-CMTM6 interaction and develop anti-tumor anti-CMTM6 nanobody".ACTA PHARMACOLOGICA SINICA (2022):10.

入库方式： OAI收割

来源：上海药物研究所

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