Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response
Immune checkpoint inhibitors (ICIs) have advanced the treatment of non-small cell lung cancer (NSCLC). This study evaluates the predictive value of CD8<sup>+</sup> T cell exhaustion in patients with lung adenocarcinoma treated with ICIs. By analyzing tumor samples from 166 patients through multiplex immunofluorescence, we quantify tumor-infiltrating lymphocytes (TILs) expressing exhaustion markers programmed cell death-1 (PD1), lymphocyte activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell immunoglobulin and mucin domain 3 (TIM3). Their co-expression is associated with ICI resistance, irrespective of programmed cell death ligand-1 (PD-L1) status. We also identify a 25-gene signature indicative of CD8<sup>+</sup> T cell exhaustion with high predictive accuracy for ICI response. Validated using several datasets from various clinical trials, this signature accurately predicts ICI responsiveness. Our findings highlight T cell exhaustion's significance in lung adenocarcinoma responses to ICIs and suggest the 25-gene signature as a potential universal biomarker to reinforce precision medicine. This was registered under Clinical Trial registration number NCT02534649.
Authors
- Diego Teyssonneau (ORCID: https://orcid.org/0000-0002-9687-3759)
- Florent Peyraud (ORCID: https://orcid.org/0000-0001-7438-2847)
- Sylvestre Le Moulec (ORCID: https://orcid.org/0000-0003-4189-0890)
- Alban Bessede
- Lucile Vanhersecke (ORCID: https://orcid.org/0000-0001-7733-7806)
- Coriolan Lebreton (ORCID: https://orcid.org/0000-0002-4275-1721)
- Bérengère Dadone‐Montaudié (ORCID: https://orcid.org/0000-0002-0339-4602)
- Laïla Belcaid (ORCID: https://orcid.org/0000-0001-8062-1533)
- Jean-Philippe Guégan
- Oren Lara (ORCID: https://orcid.org/0009-0007-0060-4217)
- Lola‐Jade Palmieri (ORCID: https://orcid.org/0000-0002-8540-9344)
- Laura Leroy (ORCID: https://orcid.org/0000-0002-2446-0955)
- Thomas Grellety (ORCID: https://orcid.org/0000-0001-5316-1420)
- Maxime Brunet (ORCID: https://orcid.org/0000-0002-7517-4529)
- Guilhem Roubaud
- Ikbel Achour (ORCID: https://orcid.org/0000-0001-6103-4069)
- Mathilde Cabart (ORCID: https://orcid.org/0000-0003-3132-0069)
- Christophe Rey (ORCID: https://orcid.org/0000-0001-9606-8525)
- Ezogelin Oflazoglu Gruyters
- Ophélie Odin (ORCID: https://orcid.org/0009-0009-2665-9990)
- Emma Clot
- Sophie Cousin
- Antoine Italiano
Institutions
- University of Copenhagen (DK)
- Centre Hospitalier Universitaire de Nice (FR)
- AstraZeneca (Singapore) (SG)
- Centre Hospitalier de la Côte Basque (FR)
- AstraZeneca (Switzerland) (CH)
- Institut Bergonié (FR)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101831
- Citations
- 24
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 6.78
Funders
- AstraZeneca
- Roche
- Conseil Régional Aquitaine