Soluble PD-L1 as a biomarker in malignant melanoma and checkpoint blockade

Abstract

Blockade of the pathway including Programmed death-ligand 1 (PD-L1) and its receptor Programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers.  Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma.  However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood.  We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted.  Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury and cell death in melanoma cells.  Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared to healthy donors.  High pre-treatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade.  Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response.  Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade.  Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors.