Inhibition of UV-Induced Stress Signaling and Inflammatory Responses in SKH-1 Mouse Skin by Topical Small Molecule PD-L1 Blockade

The immune checkpoint ligand PD-L1 has emerged as a molecular target for skin cancer therapy and might also hold promise for preventive intervention targeting solar ultraviolet light-induced skin damage. Here we have explored the role of PD-L1 in acute keratinocytic photodamage testing the effects of small molecule pharmacological inhibition. Epidermal PD-L1 upregulation in response to chronic photodamage was established using IHC and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cSCC. Topical application of the small molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced AP-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin, also confirmed in human HaCaT reporter keratinocytes. RT-qPCR analysis revealed that BMS-202 antagonized UV-induction of inflammatory gene expression. Likewise, UV-induced cleavage of procaspase-3, a hallmark of acute skin photodamage, was attenuated by topical BMS-202. NanoString nCounterTM transcriptomic analysis confirmed downregulation of cutaneous ‘innate immunity’- and ‘inflammation’-related responses together with upregulation of ‘immune response’ pathway gene expression. Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage.