IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57470-w.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2025. "Tebentafusp, a T cell engager, promotes macrophage reprogramming and in combination with IL-2 overcomes macrophage immunosuppression in cancer," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57470-w
    DOI: 10.1038/s41467-025-57470-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57470-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57470-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Shu Shien Chin & Erik Guillen & Laurent Chorro & Sooraj Achar & Karina Ng & Susanne Oberle & Francesca Alfei & Dietmar Zehn & Grégoire Altan-Bonnet & Fabien Delahaye & Grégoire Lauvau, 2022. "T cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Michael A. Durante & Daniel A. Rodriguez & Stefan Kurtenbach & Jeffim N. Kuznetsov & Margaret I. Sanchez & Christina L. Decatur & Helen Snyder & Lynn G. Feun & Alan S. Livingstone & J. William Harbour, 2020. "Single-cell analysis reveals new evolutionary complexity in uveal melanoma," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    3. Tomi Lazarov & Sergio Juarez-Carreño & Nehemiah Cox & Frederic Geissmann, 2023. "Publisher Correction: Physiology and diseases of tissue-resident macrophages," Nature, Nature, vol. 619(7970), pages 51-51, July.
    4. Peter A. Szabo & Hanna Mendes Levitin & Michelle Miron & Mark E. Snyder & Takashi Senda & Jinzhou Yuan & Yim Ling Cheng & Erin C. Bush & Pranay Dogra & Puspa Thapa & Donna L. Farber & Peter A. Sims, 2019. "Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    5. Tomi Lazarov & Sergio Juarez-Carreño & Nehemiah Cox & Frederic Geissmann, 2023. "Physiology and diseases of tissue-resident macrophages," Nature, Nature, vol. 618(7966), pages 698-707, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Han-Ying Huang & Yan-Zhou Chen & Chuang Zhao & Xin-Nan Zheng & Kai Yu & Jia-Xing Yue & Huai-Qiang Ju & Yan-Xia Shi & Lin Tian, 2024. "Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Jeonghyeon Kwon & Haruya Kawase & Kenny Mattonet & Stefan Guenther & Lisa Hahnefeld & Jamal Shamsara & Jan Heering & Michael Kurz & Sina Kirchhofer & Cornelius Krasel & Michaela Ulrich & Margherita Pe, 2025. "Orphan G protein-coupled receptor GPRC5B controls macrophage function by facilitating prostaglandin E receptor 2 signaling," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    3. Xiaojian Lu & Yanwei Luo & Xichen Nie & Bailing Zhang & Xiaoyan Wang & Ran Li & Guangmin Liu & Qianyin Zhou & Zhizhong Liu & Liqing Fan & James M. Hotaling & Zhe Zhang & Hao Bo & Jingtao Guo, 2023. "Single-cell multi-omics analysis of human testicular germ cell tumor reveals its molecular features and microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Felix Drost & Yang An & Irene Bonafonte-Pardàs & Lisa M. Dratva & Rik G. H. Lindeboom & Muzlifah Haniffa & Sarah A. Teichmann & Fabian Theis & Mohammad Lotfollahi & Benjamin Schubert, 2024. "Multi-modal generative modeling for joint analysis of single-cell T cell receptor and gene expression data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Jeff DeMartino & Michael T. Meister & Lindy L. Visser & Mariël Brok & Marian J. A. Groot Koerkamp & Amber K. L. Wezenaar & Laura S. Hiemcke-Jiwa & Terezinha Souza & Johannes H. M. Merks & Anne C. Rios, 2023. "Single-cell transcriptomics reveals immune suppression and cell states predictive of patient outcomes in rhabdomyosarcoma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Osama Al-Dalahmah & Michael G. Argenziano & Adithya Kannan & Aayushi Mahajan & Julia Furnari & Fahad Paryani & Deborah Boyett & Akshay Save & Nelson Humala & Fatima Khan & Juncheng Li & Hong Lu & Yu S, 2023. "Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Nader Atlasy & Anna Bujko & Espen S. Bækkevold & Peter Brazda & Eva Janssen-Megens & Knut E. A. Lundin & Jørgen Jahnsen & Frode L. Jahnsen & Hendrik G. Stunnenberg, 2022. "Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Tara Chari & Lior Pachter, 2023. "The specious art of single-cell genomics," PLOS Computational Biology, Public Library of Science, vol. 19(8), pages 1-20, August.
    9. Anja Fischer & Thomas K. Albert & Natalia Moreno & Marta Interlandi & Jana Mormann & Selina Glaser & Paurnima Patil & Flavia W. Faria & Mathis Richter & Archana Verma & Sebastian T. Balbach & Rabea Wa, 2024. "Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    10. Kaitlyn A. Lagattuta & Hannah L. Park & Laurie Rumker & Kazuyoshi Ishigaki & Aparna Nathan & Soumya Raychaudhuri, 2024. "The genetic basis of autoimmunity seen through the lens of T cell functional traits," Nature Communications, Nature, vol. 15(1), pages 1-6, December.
    11. E. Koncina & M. Nurmik & V. I. Pozdeev & C. Gilson & M. Tsenkova & R. Begaj & S. Stang & A. Gaigneaux & C. Weindorfer & F. Rodriguez & M. Schmoetten & E. Klein & J. Karta & V. S. Atanasova & K. Grzyb , 2023. "IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    12. Julia Paczkowska & Ming Tang & Kyle T. Wright & Li Song & Kelsey Luu & Vignesh Shanmugam & Emma L. Welsh & Jason L. Weirather & Naomi Besson & Harrison Olszewski & Billie A. Porter & Kathleen L. Pfaff, 2024. "Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    13. Matthew P. Morrow & Elisabeth Gillespie & Albert Sylvester & Milan R. Amin & Peter C. Belafsky & Simon R. Best & Aaron D. Friedman & Adam M. Klein & David G. Lott & Ted Mau & Randal C. Paniello & Seth, 2025. "DNA immunotherapy for recurrent respiratory papillomatosis (RRP): phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    14. Augusto Faria Andrade & Alva Annett & Elham Karimi & Danai Georgia Topouza & Morteza Rezanejad & Yitong Liu & Michael McNicholas & Eduardo G. Gonzalez Santiago & Dhana Llivichuzhca-Loja & Arne Gehlhaa, 2024. "Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    15. Jani Huuhtanen & Liang Chen & Emmi Jokinen & Henna Kasanen & Tapio Lönnberg & Anna Kreutzman & Katriina Peltola & Micaela Hernberg & Chunlin Wang & Cassian Yee & Harri Lähdesmäki & Mark M. Davis & Sat, 2022. "Evolution and modulation of antigen-specific T cell responses in melanoma patients," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    16. Siwei Luo & Amber Notaro & Lan Lin, 2025. "ATLAS-seq: a microfluidic single-cell TCR screen for antigen-reactive TCRs," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    17. Jingyi Xie & Daniel G. Chen & William Chour & Rachel H. Ng & Rongyu Zhang & Dan Yuan & Jongchan Choi & Michaela McKasson & Pamela Troisch & Brett Smith & Lesley Jones & Andrew Webster & Yusuf Rasheed , 2025. "APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    18. Khanyisile Kgoadi & Prashant Bajpai & Chris C. Ibegbu & Hedwin Kitdorlang Dkhar & Ana Beatriz Enriquez & Stanzin Dawa & Sushma K. Cribbs & Jyothi Rengarajan, 2025. "Alveolar macrophages from persons with HIV mount impaired TNF signaling networks to M. tuberculosis infection," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    19. Alexander Coulton & Jun Murai & Danwen Qian & Krupa Thakkar & Claire E. Lewis & Kevin Litchfield, 2024. "Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    20. Denise Lau & Sonal Khare & Michelle M. Stein & Prerna Jain & Yinjie Gao & Aicha BenTaieb & Tim A. Rand & Ameen A. Salahudeen & Aly A. Khan, 2022. "Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57470-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.