Vγ1 γδ T cells steer airway macrophages toward a profibrotic response in an autochthonous lung cancer mouse model
γδ T cells are important for host defense at the respiratory mucosa, acting directly or through interactions with other cells. However, how γδ T cells influence other immune cells in the lung remains unclear. Using a genetically engineered mouse model of lung cancer, we show that tumors drive expansion of both CD27<sup>+</sup> and CD27<sup>-</sup> γδ T cells. Advanced microscopy techniques indicated that CD27<sup>-</sup> γδ T cells are enriched in tumors, whereas CD27<sup>+</sup> γδ T cells are more prone to interact with macrophages in tumor-associated adventitial cuffs. SiglecF<sup>low</sup> profibrotic airway macrophages were more prevalent in lung tumor-bearing mice than tumor-free mice. This profibrotic subset was reduced in lungs when the cancer model was crossed to <i>Tcrd</i> knockout mice or treated with Vγ1-depleting antibodies but not in <i>TcrgV4/6</i> knockout mice. Thus, our findings implicate Vγ1 γδ T cells in driving tumor-associated airway macrophage functional imprinting. Determining the translatability to human health may offer new avenues for refining patient management and immunotherapeutic strategies.
Authors
- Lynn McGarry (ORCID: https://orcid.org/0000-0002-7055-2615)
- Björn Kruspig (ORCID: https://orcid.org/0000-0002-1712-5411)
- Judith Secklehner (ORCID: https://orcid.org/0000-0003-0005-3535)
- Kai Rakovic (ORCID: https://orcid.org/0000-0002-0676-1973)
- Frédéric Fercoq (ORCID: https://orcid.org/0000-0002-4825-024X)
- Marco De Donatis (ORCID: https://orcid.org/0000-0003-2951-5844)
- Seth B. Coffelt (ORCID: https://orcid.org/0000-0003-2257-2862)
- Robert Wiesheu (ORCID: https://orcid.org/0000-0002-2079-4413)
- Calum C. Bain (ORCID: https://orcid.org/0000-0001-8884-327X)
- Leo M. Carlin (ORCID: https://orcid.org/0000-0001-7172-5234)
- Graeme M. Clark (ORCID: https://orcid.org/0000-0002-5543-2789)
- Amanda J. McFarlane
- Ryan Corbyn (ORCID: https://orcid.org/0000-0002-6488-0495)
- Lindsey W. G. Arnott
- Ya-Ching Hsieh (ORCID: https://orcid.org/0000-0003-2715-669X)
- Kristina Kirschner
- Colin Nixon
- Robin Shaw
- Sarah Laing
- Ximena L. Raffo-Iraolagoitia
- John B. G. Mackey
- Crispin Miller
- John Le Quesne
Institutions
- NHS Greater Glasgow and Clyde (GB)
- Cancer Research UK (GB)
- MRC Centre for Regenerative Medicine (GB)
- Imperial College London (GB)
- University of Glasgow (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2026-03-04
- DOI
- https://doi.org/10.1126/sciadv.adu8802
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.00