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

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; Chong Sun

doi:10.1016/j.ccell.2023.08.008

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

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 BroeksElke 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, Chong Sun

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1817-1828.e9
Number of pages	11
Journal	Cancer Cell
Volume	41
Issue number	10
Early online date	31 Aug 2023
DOIs	https://doi.org/10.1016/j.ccell.2023.08.008
Publication status	Published - 9 Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

We would like to express our gratitude to the members of the Sun and Schumacher laboratories for their valuable discussions. We also extend our thanks to the core facilities at German Cancer Research Center (DKFZ) Heidelberg, including Flow Cytometry, Genomics and Proteomics, Light Microscopy, Center for Pre-clinical Research, and NKI-AVL core facilities Flow Cytometry, Genomics, Molecular Pathology & Biobanking (CFMPB), for their technical support and provision of biobank materials. We are grateful to F. Momburg for kindly sharing reagents. This work was supported by startup funding from National Center for Tumor Diseases ( NCT ) and DKFZ Heidelberg , DKFZ-MOST ( Israel Ministry of Science and Technology ) cooperation program (Ca 208), and European Union ( ERC , DRILL , 101078722 ) (to C.S.), The Queen Wilhelmina Cancer Research Award and European Union ( ERC , SENSIT , 742259 ) (to T.N.M.S.) (Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council . Neither the European Union nor the granting authority can be held responsible for them), NWO (Dutch Research Council) Rubicon Fellowship (452182318), Cancer Research Institute ( CRI ) Irvington Fellowship (#3441) (to R.M.), NWO Vici Grant ( 016.Vici.170.033 ), the Cancer Genomics Center (CGC.nl), and Ammodo KNAW Award 2015 for Biomedical Sciences (to T.R.B.), the NWO supported X-omics Road Map program ( 184.034.019 ) (to A.J.R.H.), the Institute for Chemical Immunology , an NWO Gravitation project (to T.N.M.S. and A.J.R.H.), and the German Research Foundation ( CRC 1530 ) (to S.S.).

Funders	Funder number
DKFZ Heidelberg
DKFZ-MOST
DRILL	101078722
National Center for Tumor Diseases
Queen Wilhelmina Cancer Research Award
SENSIT	742259
Cancer Research Institute
Cancer Genomics Centre	184.034.019
European Commission
European Research Council
Deutsche Forschungsgemeinschaft	CRC 1530
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	452182318
Ministry of Science and Technology, Israel	Ca 208
Chulabhorn Research Institute	3441
Nationales Centrum für Tumorerkrankungen Heidelberg

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2023.08.008Licence: CC BY

PIIS1535610823002842Final published version, 3.05 MBLicence: CC BY

Cite this

Miao, B., Hu, Z., Mezzadra, R., Hoeijmakers, L., Fauster, A., Du, S., Yang, Z., Sator-Schmitt, M., Engel, H., Li, X., Broderick, C., Jin, G., Gomez-Eerland, R., Rozeman, L., Lei, X., Matsuo, H., Yang, C., Hofland, I., Peters, D., ... Sun, C. (2023). CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1. Cancer Cell, 41(10), 1817-1828.e9. https://doi.org/10.1016/j.ccell.2023.08.008

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abstract = "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.",

author = "Beiping Miao and Zhaoqing Hu and Riccardo Mezzadra and Lotte Hoeijmakers and Astrid Fauster and Shangce Du and Zhi Yang and Melanie Sator-Schmitt and Helena Engel and Xueshen Li and Caroline Broderick and Guangzhi Jin and Raquel Gomez-Eerland and Lisette Rozeman and Xin Lei and Hitoshi Matsuo and Chen Yang and Ingrid Hofland and Dennis Peters and Annegien Broeks and Elke Laport and Annika Fitz and Xiyue Zhao and Mahmoud, {Mohamed A A} and Xiujian Ma and Sandrine Sander and Hai-Kun Liu and Guoliang Cui and Yu Gan and Wei Wu and Yanling Xiao and Heck, {Albert J R} and Wenxian Guan and Lowe, {Scott W} and Horlings, {Hugo M} and Cun Wang and Brummelkamp, {Thijn R} and Blank, {Christian U} and Schumacher, {Ton N M} and Chong Sun",

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Miao, B, Hu, Z, Mezzadra, R, Hoeijmakers, L, Fauster, A, Du, S, Yang, Z, Sator-Schmitt, M, Engel, H, Li, X, Broderick, C, Jin, G, Gomez-Eerland, R, Rozeman, L, Lei, X, Matsuo, H, Yang, C, Hofland, I, Peters, D, Broeks, A, Laport, E, Fitz, A, Zhao, X, Mahmoud, MAA, Ma, X, Sander, S, Liu, H-K, Cui, G, Gan, Y, Wu, W, Xiao, Y, Heck, AJR, Guan, W, Lowe, SW, Horlings, HM, Wang, C, Brummelkamp, TR, Blank, CU, Schumacher, TNM & Sun, C 2023, 'CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1', Cancer Cell, vol. 41, no. 10, pp. 1817-1828.e9. https://doi.org/10.1016/j.ccell.2023.08.008

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AU - Miao, Beiping

AU - Hu, Zhaoqing

AU - Mezzadra, Riccardo

AU - Hoeijmakers, Lotte

AU - Fauster, Astrid

AU - Du, Shangce

AU - Yang, Zhi

AU - Sator-Schmitt, Melanie

AU - Engel, Helena

AU - Li, Xueshen

AU - Broderick, Caroline

AU - Jin, Guangzhi

AU - Gomez-Eerland, Raquel

AU - Rozeman, Lisette

AU - Lei, Xin

AU - Matsuo, Hitoshi

AU - Yang, Chen

AU - Hofland, Ingrid

AU - Peters, Dennis

AU - Broeks, Annegien

AU - Laport, Elke

AU - Fitz, Annika

AU - Zhao, Xiyue

AU - Mahmoud, Mohamed A A

AU - Ma, Xiujian

AU - Sander, Sandrine

AU - Liu, Hai-Kun

AU - Cui, Guoliang

AU - Gan, Yu

AU - Wu, Wei

AU - Xiao, Yanling

AU - Heck, Albert J R

AU - Guan, Wenxian

AU - Lowe, Scott W

AU - Horlings, Hugo M

AU - Wang, Cun

AU - Brummelkamp, Thijn R

AU - Blank, Christian U

AU - Schumacher, Ton N M

AU - Sun, Chong

PY - 2023/10/9

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AB - 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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