771 Increased PD-L1 expression in human skin acutely and chronically exposed to UV irradiation

Abstract

Overexpression of the ligand PD-L1 on tumor cells may represent a hallmark of tumor immune evasion, and such overexpression has been documented in several tumors including cutaneous squamous cell carcinoma (cSCC). While PD-L1/PD-1 activity in the skin has been primarily described in inflammatory models, we focus on PD-L1 expression in human keratinocytes exposed to UV irradiation. We first assessed PD-L1 expression in archived samples from acute human studies implementing different UV exposures in sun protected (SP) skin ranging from 2-3 minimal erythema doses (MED). PD-L1 expression was measured by immunohistochemistry (IHC). From the 20 samples evaluated 14 (70%) demonstrated > 5% epidermal PD-L1 expression at 24 hours. PD-L1 in dermal endothelial cells was also noted to be increased at 24 hrs. Thereafter, we determined that HaCaT cells also respond to acute UV by increasing PD-L1 protein expression in a time- and dose-dependent manner (2-4 fold over control at 24-48 hours), an effect which is markedly reduced in the presence of MEK/ERK or JNK inhibitors. Subsequently, we investigated PD-L1 expression in chronically UV exposed human skin using matched samples representing SP skin, sun damaged skin (SD), actinic keratosis (AK) and cSCC using IHC and reverse phase protein microarray technology (RPPA). The RPPA methodology revealed negligible PD-L1 expression in SP, SD and AK, with significantly measurable expression in cSCC. IHC analysis of PD-L1 in another cohort of matched samples revealed a similar profile, with negligible expression of PD-L1 in SP and SD skin, slight staining in AK (mean 4.2%, +/- 9.5), and significant staining in cSCC (mean 19.5%, +/- 26.6). These findings suggest that upregulation of PD-L1 may be induced by UV through established, pharmacologically targetable stress-signaling pathways in keratinocytes.