TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction
Background Blockade of the programmed cell death protein 1 (PD-1) immune checkpoint (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression on CD8 T cells. Because PD-1 is induced during activation of T cells, we set out to uncover regulators whose...
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e010145.full |
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| author | Gal Markel Michal J Besser Eytan Ruppin Oscar Krijgsman Daniel S Peeper Judit Díaz-Gómez Ettai Markovits David W Vredevoogd Georgi Apriamashvili Pierre L Levy Sanju Sinha Zowi R Huinen Nils L Visser Beaunelle de Bruijn Julia Boshuizen Susan E van Hal-van Veen Maarten A Ligtenberg Onno B Bleijerveld Chun-Pu Lin Santiago Duro Sánchez Juan Simon Nieto Alex van Vliet Maarten Altelaar |
| author_facet | Gal Markel Michal J Besser Eytan Ruppin Oscar Krijgsman Daniel S Peeper Judit Díaz-Gómez Ettai Markovits David W Vredevoogd Georgi Apriamashvili Pierre L Levy Sanju Sinha Zowi R Huinen Nils L Visser Beaunelle de Bruijn Julia Boshuizen Susan E van Hal-van Veen Maarten A Ligtenberg Onno B Bleijerveld Chun-Pu Lin Santiago Duro Sánchez Juan Simon Nieto Alex van Vliet Maarten Altelaar |
| author_sort | Gal Markel |
| collection | DOAJ |
| description | Background Blockade of the programmed cell death protein 1 (PD-1) immune checkpoint (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression on CD8 T cells. Because PD-1 is induced during activation of T cells, we set out to uncover regulators whose inhibition suppresses PD-1 abundance without adversely impacting on T cell activation.Methods To identify PD-1 regulators in an unbiased fashion, we performed a whole-genome, fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in primary murine CD8 T cells. A dual-readout design using the activation marker CD137 allowed us to uncouple genes involved in PD-1 regulation from those governing general T cell activation.Results We found that the inactivation of one of several members of the TMED/EMP24/GP25L/p24 family of transport proteins, most prominently TMED10, reduced PD-1 cell surface abundance, thereby augmenting T cell activity. Another client protein was cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which was also suppressed by TMED inactivation. Treatment with TMED inhibitor AGN192403 led to lysosomal degradation of the TMED-PD-1 complex and reduced PD-1 abundance in tumor-infiltrating CD8 T cells (TIL) in mice, thus reversing T cell dysfunction. Clinically corroborating these findings, single-cell RNA analyses revealed a positive correlation between TMED expression in CD8 TIL, and both a T cell dysfunction signature and lack of ICB response. Similarly, patients receiving a TIL product with high TMED expression had a shorter overall survival.Conclusion Our results uncover a novel mechanism of PD-1 regulation, and identify a pharmacologically tractable target whose inhibition suppresses PD-1 abundance and T cell dysfunction. |
| format | Article |
| id | doaj-art-b3b1db25d0594fcdad82ad2a293ad050 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b3b1db25d0594fcdad82ad2a293ad0502025-08-20T03:54:01ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-010145TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunctionGal Markel0Michal J Besser1Eytan Ruppin2Oscar Krijgsman3Daniel S Peeper4Judit Díaz-Gómez5Ettai Markovits6David W Vredevoogd7Georgi Apriamashvili8Pierre L Levy9Sanju Sinha10Zowi R Huinen11Nils L Visser12Beaunelle de Bruijn13Julia Boshuizen14Susan E van Hal-van Veen15Maarten A Ligtenberg16Onno B Bleijerveld17Chun-Pu Lin18Santiago Duro Sánchez19Juan Simon Nieto20Alex van Vliet21Maarten Altelaar22Davidoff Center and Samueli Integrative Cancer Pioneering Center, Rabin Medical Center, Petah Tikva, IsraelDepartment of Clinical Microbiology and Immunology, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel23 Cancer Data Science Laboratory, National Cancer Institute, Bethesda, Maryland, USADepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsNucleai, Tel Aviv, IsraelDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsCancer Data Science Laboratory, National Cancer Institute Center for Cancer Research, Bethesda, Maryland, USADepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsDepartment of Molecular oncology and immunology, Netherlands Cancer Institute, Oncode Institute, Amsterdam, The NetherlandsBackground Blockade of the programmed cell death protein 1 (PD-1) immune checkpoint (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression on CD8 T cells. Because PD-1 is induced during activation of T cells, we set out to uncover regulators whose inhibition suppresses PD-1 abundance without adversely impacting on T cell activation.Methods To identify PD-1 regulators in an unbiased fashion, we performed a whole-genome, fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in primary murine CD8 T cells. A dual-readout design using the activation marker CD137 allowed us to uncouple genes involved in PD-1 regulation from those governing general T cell activation.Results We found that the inactivation of one of several members of the TMED/EMP24/GP25L/p24 family of transport proteins, most prominently TMED10, reduced PD-1 cell surface abundance, thereby augmenting T cell activity. Another client protein was cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which was also suppressed by TMED inactivation. Treatment with TMED inhibitor AGN192403 led to lysosomal degradation of the TMED-PD-1 complex and reduced PD-1 abundance in tumor-infiltrating CD8 T cells (TIL) in mice, thus reversing T cell dysfunction. Clinically corroborating these findings, single-cell RNA analyses revealed a positive correlation between TMED expression in CD8 TIL, and both a T cell dysfunction signature and lack of ICB response. Similarly, patients receiving a TIL product with high TMED expression had a shorter overall survival.Conclusion Our results uncover a novel mechanism of PD-1 regulation, and identify a pharmacologically tractable target whose inhibition suppresses PD-1 abundance and T cell dysfunction.https://jitc.bmj.com/content/12/11/e010145.full |
| spellingShingle | Gal Markel Michal J Besser Eytan Ruppin Oscar Krijgsman Daniel S Peeper Judit Díaz-Gómez Ettai Markovits David W Vredevoogd Georgi Apriamashvili Pierre L Levy Sanju Sinha Zowi R Huinen Nils L Visser Beaunelle de Bruijn Julia Boshuizen Susan E van Hal-van Veen Maarten A Ligtenberg Onno B Bleijerveld Chun-Pu Lin Santiago Duro Sánchez Juan Simon Nieto Alex van Vliet Maarten Altelaar TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction Journal for ImmunoTherapy of Cancer |
| title | TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction |
| title_full | TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction |
| title_fullStr | TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction |
| title_full_unstemmed | TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction |
| title_short | TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction |
| title_sort | tmed inhibition suppresses cell surface pd 1 expression and overcomes t cell dysfunction |
| url | https://jitc.bmj.com/content/12/11/e010145.full |
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