ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality
Cancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2532662 |
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| author | Annina Kurzay Sara Fresnillo Saló Anne Rahbech Tina Seremet Cecilie Oelvang Madsen Christopher Aled Chamberlain Emilie Bülow Jensen Viet Thy Luu Özcan Met Marlies J W Peeters Per thor Straten |
| author_facet | Annina Kurzay Sara Fresnillo Saló Anne Rahbech Tina Seremet Cecilie Oelvang Madsen Christopher Aled Chamberlain Emilie Bülow Jensen Viet Thy Luu Özcan Met Marlies J W Peeters Per thor Straten |
| author_sort | Annina Kurzay |
| collection | DOAJ |
| description | Cancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells remains poorly understood. Here, we demonstrate that ProS1-MerTK signaling is upregulated in activated CD4 T cells, where it enhances central memory formation, metabolic fitness, and proliferation. Mechanistically, ProS1-MerTK signaling was linked to type 1 immune responses, suggesting a regulatory role in CD4 T cell polarization. Using CRISPR-Cas9-mediated knockout, we found that loss of MerTK reduced CD4 T cell fitness, function, and polarization. Furthermore, when ProS1 was added during the expansion of tumor-infiltrating lymphocytes (TILs) from advanced melanoma biopsies, it showed potential to promote favorable CD4 T cell memory and helper phenotypes, increase stemness, and reduce exhaustion – features associated with improved responses to ACT. These findings establish ProS1-MerTK as a key pathway for modulating CD4 T cell functionality and highlight its therapeutic potential to enhance TIL-based ACT outcomes. |
| format | Article |
| id | doaj-art-11331beffbf24084b248a39546c6ffda |
| institution | Kabale University |
| issn | 2162-402X |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-11331beffbf24084b248a39546c6ffda2025-08-20T03:27:21ZengTaylor & Francis GroupOncoImmunology2162-402X2025-12-0114110.1080/2162402X.2025.2532662ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionalityAnnina Kurzay0Sara Fresnillo Saló1Anne Rahbech2Tina Seremet3Cecilie Oelvang Madsen4Christopher Aled Chamberlain5Emilie Bülow Jensen6Viet Thy Luu7Özcan Met8Marlies J W Peeters9Per thor Straten10National Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkNational Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, DenmarkCancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells remains poorly understood. Here, we demonstrate that ProS1-MerTK signaling is upregulated in activated CD4 T cells, where it enhances central memory formation, metabolic fitness, and proliferation. Mechanistically, ProS1-MerTK signaling was linked to type 1 immune responses, suggesting a regulatory role in CD4 T cell polarization. Using CRISPR-Cas9-mediated knockout, we found that loss of MerTK reduced CD4 T cell fitness, function, and polarization. Furthermore, when ProS1 was added during the expansion of tumor-infiltrating lymphocytes (TILs) from advanced melanoma biopsies, it showed potential to promote favorable CD4 T cell memory and helper phenotypes, increase stemness, and reduce exhaustion – features associated with improved responses to ACT. These findings establish ProS1-MerTK as a key pathway for modulating CD4 T cell functionality and highlight its therapeutic potential to enhance TIL-based ACT outcomes.https://www.tandfonline.com/doi/10.1080/2162402X.2025.2532662Adoptive cell therapyimmunotherapymelanomaT cellTAM-receptortumour infiltrating lymphocyte |
| spellingShingle | Annina Kurzay Sara Fresnillo Saló Anne Rahbech Tina Seremet Cecilie Oelvang Madsen Christopher Aled Chamberlain Emilie Bülow Jensen Viet Thy Luu Özcan Met Marlies J W Peeters Per thor Straten ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality OncoImmunology Adoptive cell therapy immunotherapy melanoma T cell TAM-receptor tumour infiltrating lymphocyte |
| title | ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality |
| title_full | ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality |
| title_fullStr | ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality |
| title_full_unstemmed | ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality |
| title_short | ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality |
| title_sort | pros1 mertk signaling in cd4 t cells implications for til expansion and functionality |
| topic | Adoptive cell therapy immunotherapy melanoma T cell TAM-receptor tumour infiltrating lymphocyte |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2532662 |
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