Guégan et al. analyzed tumor samples from 166 lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICI) to evaluate the predictive value of CD8+ T cell exhaustion on responsiveness to immunotherapy. Using multiplex immunofluorescence, CD8+ TILs co-expressing high levels of checkpoint molecules PD-1, LAG3, TIGIT, or TIM3 were associated with ICI resistance, irrespective of PD-L1 levels. In addition, a 25-gene CD8+ T cell exhaustion signature was identified that predicted patients’ responses to ICI (but not to TKI) therapy, which was further validated in additional external datasets, including melanoma and renal cell cancer.
Contributed by Katherine Turner
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.
Author Info: (1) Explicyte Immuno-Oncology, Bordeaux, France. (2) Explicyte Immuno-Oncology, Bordeaux, France; Department of Medicine, Institut Bergonié, Bordeaux, France. (3) Department of Pat
Author Info: (1) Explicyte Immuno-Oncology, Bordeaux, France. (2) Explicyte Immuno-Oncology, Bordeaux, France; Department of Medicine, Institut Bergonié, Bordeaux, France. (3) Department of Pathology, University Hospital Centre of Nice, Nice, France. (4) Explicyte Immuno-Oncology, Bordeaux, France; Department of Medicine, Institut Bergonié, Bordeaux, France. (5) Explicyte Immuno-Oncology, Bordeaux, France; Department of Medicine, Institut Bergonié, Bordeaux, France. (6) Department of Medicine, Institut Bergonié, Bordeaux, France. (7) Department of Medicine, Institut Bergonié, Bordeaux, France. (8) Department of Medicine, Institut Bergonié, Bordeaux, France. (9) Department of Medicine, Institut Bergonié, Bordeaux, France. (10) Department of Medicine, Institut Bergonié, Bordeaux, France. (11) Department of Medicine, Institut Bergonié, Bordeaux, France. (12) Explicyte Immuno-Oncology, Bordeaux, France. (13) Explicyte Immuno-Oncology, Bordeaux, France. (14) Explicyte Immuno-Oncology, Bordeaux, France. (15) Department of Medicine, Institut Bergonié, Bordeaux, France. (16) Department of Pathology, Institut Bergonié, Bordeaux, France. (17) AstraZeneca, Rahway, NJ, USA. (18) AstraZeneca, Rahway, NJ, USA. (19) University of Copenhagen, Copenhagen, Denmark. (20) Clinique Marzet, Pau, France. (21) Centre Hospitalier de la Côte Basque, Bayonne, France. (22) Explicyte Immuno-Oncology, Bordeaux, France. (23) Department of Medicine, Institut Bergonié, Bordeaux, France. Electronic address: a.italiano@bordeaux.unicancer.fr.
