A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Clinical Cancer Research Année : 2022

A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma

Isabelle Girault
  • Fonction : Auteur
Julien Adam
  • Fonction : Auteur
Shensi Shen
Séverine Roy
  • Fonction : Auteur
Caroline Brard
Sara Faouzi
  • Fonction : Auteur
Emilie Routier
  • Fonction : Auteur
Jéremy Lupu
  • Fonction : Auteur
Sarah Warren
  • Fonction : Auteur
Kristina Sorg
  • Fonction : Auteur
Sufey Ong
  • Fonction : Auteur
Pascale Morel
  • Fonction : Auteur
Jean-Yves Scoazec
Stéphan Vagner

Résumé

Abstract Purpose: Less than 50% of patients with melanoma respond to anti–programmed cell death protein 1 (anti–PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti–PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti–PD-1 therapy. Experimental Design: PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n = 66 and validation n = 71) of samples from patients with melanoma treated with anti–PD-1±anti–CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8+ cells density, and NanoString RNA signature, were also evaluated. Results: A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71–0.77). Progression-free and overall survival were significantly longer in patients with high PLA values (P = 0.00019 and P < 0.0001, respectively). Conclusions: The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti–PD-1 efficacy.

Dates et versions

hal-04516904 , version 1 (22-03-2024)

Identifiants

Citer

Isabelle Girault, Julien Adam, Shensi Shen, Séverine Roy, Caroline Brard, et al.. A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma. Clinical Cancer Research, 2022, 28 (3), pp.518-525. ⟨10.1158/1078-0432.CCR-21-1229⟩. ⟨hal-04516904⟩
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