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

Sally E. Dickinson*, Prajakta Vaishampayan, Jana Jandova, Yuchen (Ella) Ai, Viktoria Kirschnerova, Tianshun Zhang, Valerie Calvert, Emanuel Petricoin, H. H.Sherry Chow, Chengcheng Hu, Denise Roe, Ann Bode, Clara Curiel-Lewandrowski, Georg T. Wondrak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 UV light–induced skin damage. In this study, 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 immunohistochemical and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cutaneous squamous cell carcinoma. Topical application of the small-molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced activator protein-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 nCounter 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.

Original languageEnglish
Article number100255
JournalJID Innovations
Volume4
Issue number2
DOIs
StatePublished - Mar 2024
Externally publishedYes

Keywords

  • Inflammation
  • PD-L1
  • SKH-1 mouse
  • Skin photoprotection
  • UV light

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