title: PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome.
abstract: Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8+, CD45, CD4+, CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.
authors.affiliation: Department of Surgery, University of Virginia School of Medicine , Charlottesville, VA, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Obeid
authors.affiliation: Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA, USA; Department of Pathology, University of Virginia Health Science Center, Charlottesville, VA, USA.
authors.forename: Gulsun
authors.initials: G
authors.lastname: Erdag
authors.affiliation: Department of Public Health Sciences, University of Virginia Health Science Center , Charlottesville, VA, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Smolkin
authors.affiliation: Department of Surgery, University of Virginia School of Medicine , Charlottesville, VA, USA.
authors.forename: Donna H
authors.initials: DH
authors.lastname: Deacon
authors.affiliation: Department of Pathology, University of Virginia Health Science Center , Charlottesville, VA, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Patterson
authors.affiliation: University of Virginia Health Science Center, Charlottesville, VA, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Leiping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Virginia Health Science Center , Charlottesville, VA, USA.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Bullock
authors.affiliation: Department of Surgery, University of Virginia School of Medicine , Charlottesville, VA, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
keywords: Immune checkpoint; PD-1; PD-L1; PD-L2; immune infiltrates; metastatic melanoma; patient outcomes; tumor-infiltrating lymphocytes