Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response
Jean‐Philippe Guégan, Florent Peyraud, Bérengère Dadone‐Montaudié, Diego Teyssonneau, Lola‐Jade Palmieri, Emma Clot, Sophie Cousin, Guilhem Roubaud, Mathilde Cabart, Laura Leroy, Coriolan Lebreton, Christophe Rey, Oren Lara, Ophélie Odin, Maxime Brunet, Lucile Vanhersecke, Ezogelin Oflazoglu Gruyters, Ikbel Achour, Leila Belcaid, Sylvestre Le Moulec, Thomas Grellety, Alban Bessede, Antoine Italiano
Abstract
Immune checkpoint inhibitors (ICIs) have advanced the treatment of non-small cell lung cancer (NSCLC). This study evaluates the predictive value of CD8 + 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 + 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 . • Checkpoint molecules expression on CD8 + cells impacts immunotherapy efficiency • A 25-gene signature was derived to predict exhausted T cells’ abundance • Exhaustion gene signature predicts outcomes of immunotherapy treatment In a cohort of 166 patients with lung adenocarcinoma, Guégan et al. show that CD8 + T cell exhaustion is associated with resistance to immune checkpoint inhibitor. They further develop a gene signature that can predict the exhaustion status of CD8 + T cells and the outcome of immunotherapy.