Tracking the evolution of circulating exosomal‐PD‐L1 to monitor melanoma patients

Abstract

In the era of immunotherapies there is an urgent need to implement the use of circulating biomarkers in clinical practice to facilitate personalized therapy and to predict treatment response. We conducted a prospective study to evaluate the usefulness of circulating exosomal-PD-L1 in melanoma patients' follow-up. We studied the dynamics of exosomal-PD-L1 from 100 melanoma patients by using an enzyme-linked immunosorbent assay. We found that PD-L1 was secreted through exosomes by melanoma cells. Exosomes carrying PD-L1 had immunosuppressive properties since they were as efficient as the cancer cell from which they derive at inhibiting T-cell activation. In plasma from melanoma patients, the level of PD-L1 (n= 30, median 64.26 pg/mL) was significantly higher in exosomes compared to soluble PD-L1 (n= 30, 0.1 pg/mL). Furthermore, exosomal-PD-L1 was detected in all patients whereas only 67% of tumour biopsies were PD-L1 positive. Although baseline exosomal-PD-L1 levels were not associated with clinic-pathologic characteristics, their variations after the cures (ΔExoPD-L1) correlated with the tumour response to treatment. A ΔExoPD-L1 cut-off of > 100 was defined, yielding an 83% sensitivity, a 70% specificity, a 91% positive predictive value and 54% negative predictive values for disease progression. The use of the cut-off allowed stratification in two groups of patients statistically different concerning overall survival and progression-free survival. PD-L1 levels in circulating exosomes seem to be a more reliable marker than PD-L1 expression in tumour biopsies. Monitoring of circulating exosomal-PD-L1 may be useful to predict the tumour response to treatment and clinical outcome. ARTICLE HISTORY

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

“…Soluble PD-L1 (sPD-L1) is frequently detected in the blood of cancer patients. Three mechanisms can contribute to the release of PD-L1 into circulation: alternatively spliced transcripts [ 153 , 154 ], release of PD-L1 associated with extracellular vesicles such as exosomes [ 155 , 156 ] and proteolytical cleavage from the surface of PD-L1-expressing cancer- and non-cancer cells [ 157 ].…”

Exosomal PD-L1 Derived From Osteosarcoma is Associated With Pulmonary Metastasis for Patients With Osteosarcoma

“…Several studies revealed the presence of PD-L1 in exosomes isolated from blood samples of patients with cancer, and the level of PD-L1 correlates with pathological features of these patients [23,24,39,40]. Chen et al reported metastatic melanomas released exosomes, delivering PD-L1 on their surface.…”

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

“…Elevated basal levels of soluble PD-L1 in the plasma of melanoma patients was associated with progressive disease [95]. Furthermore, the measurement of PD-L1 in EV could help to predict the response to ICI, demonstrating an advantage of the detection in EV over tumor biopsies [96]. Melanoma patients responding to pembrolizumab could be distinguished from non-responders by increased levels of EV PD-L1 at 3 to 6 weeks after the start of therapy [97].…”