| Autor: |
Lone AM; Department of Cancer Immunology, Institute of Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.; K.G. Jebsen Centre for Cancer Immunotherapy and K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0317 Oslo, Norway.; Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway., Giansanti P; Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, Netherlands.; Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising 85354, Germany., Jørgensen MJ; K.G. Jebsen Centre for Cancer Immunotherapy and K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0317 Oslo, Norway.; Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway., Gjerga E; Joint Research Centre for Computational Biomedicine (JRC-Combine), RWTH-Aachen University Hospital, Faculty of Medicine, Aachen 52074, Germany.; Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Bioquant, Heidelberg University, Heidelberg 69120, Germany., Dugourd A; Joint Research Centre for Computational Biomedicine (JRC-Combine), RWTH-Aachen University Hospital, Faculty of Medicine, Aachen 52074, Germany.; Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Bioquant, Heidelberg University, Heidelberg 69120, Germany., Scholten A; Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, Netherlands., Saez-Rodriguez J; Joint Research Centre for Computational Biomedicine (JRC-Combine), RWTH-Aachen University Hospital, Faculty of Medicine, Aachen 52074, Germany.; Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Bioquant, Heidelberg University, Heidelberg 69120, Germany., Heck AJR; Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, Netherlands., Taskén K; Department of Cancer Immunology, Institute of Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.; K.G. Jebsen Centre for Cancer Immunotherapy and K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, 0317 Oslo, Norway.; Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway. |
| Abstrakt: |
Prostaglandin E 2 (PGE 2 ) promotes an immunosuppressive microenvironment in cancer, partly by signaling through four receptors (EP 1 , EP 2 , EP 3 , and EP 4 ) on T cells. Here, we comprehensively characterized PGE 2 signaling networks in helper, cytotoxic, and regulatory T cells using a phosphoproteomics and phosphoflow cytometry approach. We identified ~1500 PGE 2 -regulated phosphosites and several important EP 1–4 signaling nodes, including PKC, CK2, PKA, PI3K, and Src. T cell subtypes exhibited distinct signaling pathways, with the strongest signaling in EP 2 -stimulated CD8 + cells. EP 2 and EP 4 , both of which signal through G αs , induced similar signaling outputs, but with distinct kinetics and intensity. Functional predictions from the observed phosphosite changes revealed PGE 2 regulation of key cellular and immunological processes. Last, network modeling suggested signal integration between the receptors and a substantial contribution from G protein–independent signaling. This study offers a comprehensive view of the different PGE 2 -regulated phosphoproteomes in T cell subsets, providing a valuable resource for further research on this physiologically and pathophysiologically important signaling system. |
