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

Esra Güç, Agatha Treveil, Emma Leach, Anna Broomfield, Antonio Camera, James Clubley, Paula Nieto Garcia, Anastasiya Kazachenka, Rahul Khanolkar, Luis Carpio, Holger Heyn, Jessica C. Hassel, Joseph J. Sacco, Sarah Stanhope, Laura Collins, Josep M. Piulats, Koustubh Ranade and Adel Benlahrech ()
Additional contact information
Esra Güç: Immunocore Ltd
Agatha Treveil: Immunocore Ltd
Emma Leach: Immunocore Ltd
Anna Broomfield: Immunocore Ltd
Antonio Camera: Immunocore Ltd
James Clubley: Immunocore Ltd
Paula Nieto Garcia: Centro Nacional de Análisis Genómico (CNAG)
Anastasiya Kazachenka: Immunocore Ltd
Rahul Khanolkar: Immunocore Ltd
Luis Carpio: Institut Català d’Oncologia (ICO)—Cancer Immunotherapy Group at’Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat
Holger Heyn: Universitat de Barcelona (UB), ICREA
Jessica C. Hassel: Heidelberg University, NCT Heidelberg
Joseph J. Sacco: University of Liverpool & Clatterbridge Cancer Centre
Sarah Stanhope: Immunocore Ltd
Laura Collins: Immunocore Ltd
Josep M. Piulats: Institut Català d’Oncologia (ICO)—Cancer Immunotherapy Group at’Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat
Koustubh Ranade: Immunocore Ltd
Adel Benlahrech: Immunocore Ltd

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-57470-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57470-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-57470-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().