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s41467-025-57470-w.pdf (2.76 MB)

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2025-03-10

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cc-by-nc-nd (c) Güç et al., 2025
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/222076

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

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https://doi.org/10.1038/s41467-025-57470-w

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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.

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Terapèutica, Càncer

Matèries (anglès)

Therapeutics, Cancer

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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GÜÇ, Esra, TREVEIL, Agatha, LEACH, Emma, BROOMFIELD, Anna, CAMERA, Antonio, CLUBLEY, James, NIETO GARCÍA, Paula, KAZACHENKA, Anastasiya, KHANOLKAR, Rahul, CARPIO, Luis p. del, HEYN, Holger, HASSEL, Jessica c., SACCO, Joseph j., STANHOPE, Sarah, COLLINS, Laura, PIULATS, Josep m., RANADE, Koustubh, BENLAHRECH, Adel. Tebentafusp, a T cell engager, promotes macrophage reprogramming and in combination with IL-2 overcomes macrophage immunosuppression in cancer. _Nature Communications_. 2025. Vol. 16, núm. 2374. [consulta: 21 de gener de 2026]. ISSN: 2041-1723. [Disponible a: https://hdl.handle.net/2445/222076]

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