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Tebentafusp, a T cell engager, promotes macrophage reprogramming and in combination with IL-2 overcomes macrophage immunosuppression in cancer

Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*0...

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Main Authors: Güç, Esra (Author) , Treveil, Agatha (Author) , Leach, Emma (Author) , Broomfield, Anna (Author) , Camera, Antonio (Author) , Clubley, James (Author) , Nieto Garcia, Paula (Author) , Kazachenka, Anastasiya (Author) , Khanolkar, Rahul (Author) , del Carpio, Luis (Author) , Heyn, Holger (Author) , Hassel, Jessica C. (Author) , Sacco, Joseph J. (Author) , Stanhope, Sarah (Author) , Collins, Laura (Author) , Piulats, Josep M. (Author) , Ranade, Koustubh (Author) , Benlahrech, Adel (Author)
Format: Article (Journal)
Language:English
Published: 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-16
ISSN:2041-1723
DOI:10.1038/s41467-025-57470-w
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-57470-w
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-57470-w
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Author Notes:Esra Güç, Agatha Treveil, Emma Leach, Anna Broomfield, Antonio Camera, James Clubley, Paula Nieto Garcia, Anastasiya Kazachenka, Rahul Khanolkar, Luis del Carpio, Holger Heyn, Jessica C. Hassel, Joseph J. Sacco, Sarah Stanhope, Laura Collins, Josep M. Piulats, Koustubh Ranade & Adel Benlahrech
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Summary:Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*02:01+ adult patients with mUM. Here we investigate the impact of tumor-associated macrophages (TAM) on ImmTAC activity. In vitro, M2 macrophages inhibit ImmTAC-mediated tumor-killing in a dose-dependent and contact-dependent manner. Accordingly, high baseline intratumoral TAM-to-T cell ratios correlate with shorter OS (HR = 2.09, 95% CI, 1.31-3.33, p = 0.002) in tebentafusp-treated mUM patients from a phase 2 trial. By contrast, IL-2 conditioning of T cells overcomes M2 macrophage-mediated suppression in vitro, while ImmTAC treatment leads to M2-to-M1 macrophage reprogramming both in vitro and in tebentafusp-treated mUM patients. Overall, we show that tebentafusp reshapes the tumor microenvironment to enhance anti-tumor T cell activity, whilst combining tebentafusp with IL-2 may enhance benefit in patients with high levels of TAM.
Item Description:Online veröffentlicht: 10. März 2025
Gesehen am 05.11.2025
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-57470-w

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