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

Abstract

<div>AbstractPurpose:<p>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<sup>+</sup> 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.</p>Experimental Design:<p>PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory <i>n</i> = 66 and validation <i>n</i> = 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<sup>+</sup> cells density, and NanoString RNA signature, were also evaluated.</p>Results:<p>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 (<i>P</i> = 0.00019 and <i>P</i> < 0.0001, respectively).</p>Conclusions:<p>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.</p></div>