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CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a...

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Main Authors: Miao, Beiping (Author) , Hu, Zhaoqing (Author) , Mezzadra, Riccardo (Author) , Hoeijmakers, Lotte (Author) , Fauster, Astrid (Author) , Du, Shangce (Author) , Yang, Zhi (Author) , Sator-Schmitt, Melanie (Author) , Engel, Helena (Author) , Li, Xueshen (Author) , Broderick, Caroline (Author) , Jin, Guangzhi (Author) , Gomez-Eerland, Raquel (Author) , Rozeman, Lisette (Author) , Lei, Xin (Author) , Matsuo, Hitoshi (Author) , Yang, Chen (Author) , Hofland, Ingrid (Author) , Peters, Dennis (Author) , Broeks, Annegien (Author) , Laport, Elke (Author) , Fitz, Annika (Author) , Zhao, Xiyue (Author) , Mahmoud, Mohamed A. A. (Author) , Ma, Xiujian (Author) , Sander, Sandrine (Author) , Liu, Hai-Kun (Author) , Cui, Guoliang (Author) , Gan, Yu (Author) , Wu, Wei (Author) , Xiao, Yanling (Author) , Heck, Albert J. R. (Author) , Guan, Wenxian (Author) , Lowe, Scott W. (Author) , Horlings, Hugo M. (Author) , Wang, Cun (Author) , Brummelkamp, Thijn R. (Author) , Blank, Christian U. (Author) , Schumacher, Ton N. M. (Author) , Sun, Chong (Author)
Format: Article (Journal)
Language:English
Published: 7 September 2023
In: Cancer cell
Year: 2023, Volume: 41, Issue: 10, Pages: 1817-1828.e9
ISSN:1878-3686
DOI:10.1016/j.ccell.2023.08.008
Online Access:Resolving-System, kostenfrei, Volltext: https://doi.org/10.1016/j.ccell.2023.08.008
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610823002842
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Author Notes:Beiping Miao, Zhaoqing Hu, Riccardo Mezzadra, Lotte Hoeijmakers, Astrid Fauster, Shangce Du, Zhi Yang, Melanie Sator-Schmitt, Helena Engel, Xueshen Li, Caroline Broderick, Guangzhi Jin, Raquel Gomez-Eerland, Lisette Rozeman, Xin Lei, Hitoshi Matsuo, Chen Yang, Ingrid Hofland, Dennis Peters, Annegien Broeks, Elke Laport, Annika Fitz, Xiyue Zhao, Mohamed A. A. Mahmoud, Xiujian Ma, Sandrine Sander, Hai-kun Liu, Guoliang Cui, Yu Gan, Wei Wu, Yanling Xiao, Albert J. R. Heck, Wenxian Guan, Scott W. Lowe, Hugo M. Horlings, Cun Wang, Thijn R. Brummelkamp, Christian U. Blank, Ton N. M. Schumacher, and Chong Sun

MARC

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245 1 0 |a CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1  |c Beiping Miao, Zhaoqing Hu, Riccardo Mezzadra, Lotte Hoeijmakers, Astrid Fauster, Shangce Du, Zhi Yang, Melanie Sator-Schmitt, Helena Engel, Xueshen Li, Caroline Broderick, Guangzhi Jin, Raquel Gomez-Eerland, Lisette Rozeman, Xin Lei, Hitoshi Matsuo, Chen Yang, Ingrid Hofland, Dennis Peters, Annegien Broeks, Elke Laport, Annika Fitz, Xiyue Zhao, Mohamed A. A. Mahmoud, Xiujian Ma, Sandrine Sander, Hai-kun Liu, Guoliang Cui, Yu Gan, Wei Wu, Yanling Xiao, Albert J. R. Heck, Wenxian Guan, Scott W. Lowe, Hugo M. Horlings, Cun Wang, Thijn R. Brummelkamp, Christian U. Blank, Ton N. M. Schumacher, and Chong Sun 
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520 |a The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses. 
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