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

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.

Extensive-stage small-cell lung cancer in patients receiving atezolizumab plus carboplatin–etoposide: stratification of outcome based on a composite score that combines gene expression profiling and immune characterization of microenvironment

“…In line with these findings, in our case series, the SCLC-A subtype is characterized by the highest percentage of PD-1+T cells in close proximity to PD-L1-positive macrophages and tumor cells. These results are in line with observations in metastatic melanoma where the proximity between PD-1 and PD-L1 correlates with response to ICI, 35 and suggests the importance of an exhausted TME in the response to immunotherapy in ES-SCLC. Accordingly, we showed that patients with high expression of the exhausted CD8-related gene signature have a better outcome.…”

PD-L1 methylation restricts PD-L1/PD-1 interactions to control cancer immune surveillance

“…Current treatments that target the PD-1/PD-L1 pathway do so by blocking their interactions; thus, checkpoint interaction status may present a key mechanism-based prognostic and predictive biomarker, replacing conventional protein expression readouts for stratifying patients with immune checkpoint inhibitors (ICIs). Recent studies have shown that the PD-1/PD-L1 colocation score is highly predictive of the response to anti-PD-1/PD-L1 immunotherapy (12)(13)(14). Hence, it is important to understand the mechanistic pathways that control PD-1/PD-L1 interactions, which can offer a molecular basis for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade in patients with cancer.…”

Analysis of the clinical efficacy and safety of anti‐PD‐1 immune checkpoint inhibitors in locally advanced nasopharyngeal cancer

“…PD-L1 is currently a well-established predictive marker used in clinical practice. Girault found that melanoma patients with high expression levels of PD-1 and PD-L1 treated with anti-PD-1 inhibitors experienced longer OS 43 ; tumor mutational burden (TMB), which is another hotspot in the determination of predictive markers for immunotherapy, was found to be associated with the risk of tumor recurrence and the efficacy of oncology treatment. 44,45 Xu investigated the prognostic relationship between EBV DNA and the efficacy of anti-PD-1 immune checkpoint inhibitors against NPC 46 and found a positive correlation between the two, suggesting that plasma EBV DNA may play a prognostic role in the detection of disease progression in NPC patients treated with ICIs, as well as microsatellite instability and tumor lymphocyte infiltration in further study.…”