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.

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.…”

Deciphering transcriptomic determinants of the divergent link between PD-L1 and immunotherapy efficacy

“…To better implement PD-L1 expression as a robust clinical biomarker, previous studies have primarily focused on improving the sensitivity and reproducibility of PD-L1 testing by evaluating the technical and clinicopathological correlation with PD-L1 positivity 3 – 5 or developing different means of assessing PD-L1 expression 6 – 8 . In addition, numerous groups have suggested using PD-L1 expression jointly with tumor mutation burden and CD8 + T cells to predict ICI response 9 – 11 .…”

446 HR+breast cancer: Defining innate and acquired resistance to immune checkpoint inhibitors

“…Immune checkpoint inhibitors (ICIs) have successfully been implemented in the management of other solid tumors like melanoma. 2 Conversely, the clinical experience with single-agent ICIs has been disappointing in patients with HR + BC 3 , at least in part reflecting a limited immune infiltration at baseline and calling for the development of combinatorial regimens unlocking ICI efficacy in this patient population. In this setting, progress has also been hampered by the lack of a preclinical model that would faithfully recapitulated key immunobiological features of human HR + BC.…”