Activated T Cells Break Tumor Immunosuppression by Macrophage Reeducation.
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| Format: | Artículo científico |
| Langue: | en |
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Cancer discovery
2025
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| author | Trotta, Rosa Rivis, Silvia Zhao, Shikang Orban, Marie-Pauline Trusso Cafarello, Sarah Charatsidou, Iris Pozniak, Joanna Dehairs, Jonas Vanheer, Lotte Pulido Vicuna, Carlos A Boecxstaens, Veerle Bechter, Oliver Bosisio, Francesca M Swinnen, Johannes V Marine, Jean-Christophe Mazzone, Massimiliano |
| author_facet | Trotta, Rosa Rivis, Silvia Zhao, Shikang Orban, Marie-Pauline Trusso Cafarello, Sarah Charatsidou, Iris Pozniak, Joanna Dehairs, Jonas Vanheer, Lotte Pulido Vicuna, Carlos A Boecxstaens, Veerle Bechter, Oliver Bosisio, Francesca M Swinnen, Johannes V Marine, Jean-Christophe Mazzone, Massimiliano Trotta, Rosa Rivis, Silvia Zhao, Shikang Orban, Marie-Pauline Trusso Cafarello, Sarah Charatsidou, Iris Pozniak, Joanna Dehairs, Jonas Vanheer, Lotte Pulido Vicuna, Carlos A Boecxstaens, Veerle Bechter, Oliver Bosisio, Francesca M Swinnen, Johannes V Marine, Jean-Christophe Mazzone, Massimiliano |
| collection | PubMed - marine biology |
| contents | Activated T Cells Break Tumor Immunosuppression by Macrophage Reeducation. Trotta, Rosa Rivis, Silvia Zhao, Shikang Orban, Marie-Pauline Trusso Cafarello, Sarah Charatsidou, Iris Pozniak, Joanna Dehairs, Jonas Vanheer, Lotte Pulido Vicuna, Carlos A Boecxstaens, Veerle Bechter, Oliver Bosisio, Francesca M Swinnen, Johannes V Marine, Jean-Christophe Mazzone, Massimiliano Animals Mice Humans Tumor-Associated Macrophages Tumor Microenvironment Melanoma Lymphocyte Activation Intramolecular Oxidoreductases Macrophages CD8-Positive T-Lymphocytes T-Lymphocytes Lipocalins In this study, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAM) through TNFα signaling. Mechanistically, HPGDS installs a prostaglandin D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their protumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces antitumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to αPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFα blockade sustains a protumoral environment and αPD1 resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to αPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient αPD1 treatment. Overall, we disclose a mechanism whereby T-cell activation controls the innate immune system, and we suggest HPGDS/PGD2 targeting to overcome immunotherapy resistance. In this study, we show a mechanism whereby T-cell activation controls the innate immune system and shapes the tumor microenvironment by reducing PGD2 production in TAMs. We suggest HPGDS inhibition as a promising strategy to treat refractory tumors to current immunotherapies or to overcome acquired resistance to immune checkpoint blockade. |
| format | Artículo científico |
| id | pubmed_40094380 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Cancer discovery |
| record_format | pubmed |
| spellingShingle | Activated T Cells Break Tumor Immunosuppression by Macrophage Reeducation. Trotta, Rosa Rivis, Silvia Zhao, Shikang Orban, Marie-Pauline Trusso Cafarello, Sarah Charatsidou, Iris Pozniak, Joanna Dehairs, Jonas Vanheer, Lotte Pulido Vicuna, Carlos A Boecxstaens, Veerle Bechter, Oliver Bosisio, Francesca M Swinnen, Johannes V Marine, Jean-Christophe Mazzone, Massimiliano Animals Mice Humans Tumor-Associated Macrophages Tumor Microenvironment Melanoma Lymphocyte Activation Intramolecular Oxidoreductases Macrophages CD8-Positive T-Lymphocytes T-Lymphocytes Lipocalins Activated T Cells Break Tumor Immunosuppression by Macrophage Reeducation. Trotta, Rosa Rivis, Silvia Zhao, Shikang Orban, Marie-Pauline Trusso Cafarello, Sarah Charatsidou, Iris Pozniak, Joanna Dehairs, Jonas Vanheer, Lotte Pulido Vicuna, Carlos A Boecxstaens, Veerle Bechter, Oliver Bosisio, Francesca M Swinnen, Johannes V Marine, Jean-Christophe Mazzone, Massimiliano Animals Mice Humans Tumor-Associated Macrophages Tumor Microenvironment Melanoma Lymphocyte Activation Intramolecular Oxidoreductases Macrophages CD8-Positive T-Lymphocytes T-Lymphocytes Lipocalins In this study, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAM) through TNFα signaling. Mechanistically, HPGDS installs a prostaglandin D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their protumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces antitumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to αPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFα blockade sustains a protumoral environment and αPD1 resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to αPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient αPD1 treatment. Overall, we disclose a mechanism whereby T-cell activation controls the innate immune system, and we suggest HPGDS/PGD2 targeting to overcome immunotherapy resistance. In this study, we show a mechanism whereby T-cell activation controls the innate immune system and shapes the tumor microenvironment by reducing PGD2 production in TAMs. We suggest HPGDS inhibition as a promising strategy to treat refractory tumors to current immunotherapies or to overcome acquired resistance to immune checkpoint blockade. |
| title | Activated T Cells Break Tumor Immunosuppression by Macrophage Reeducation. |
| topic | Animals Mice Humans Tumor-Associated Macrophages Tumor Microenvironment Melanoma Lymphocyte Activation Intramolecular Oxidoreductases Macrophages CD8-Positive T-Lymphocytes T-Lymphocytes Lipocalins |
| url | https://pubmed.ncbi.nlm.nih.gov/40094380/ |