Synergistic enhancement of PD-L1 expression from DNA repair dysfunction and UV exposure in xeroderma pigmentosum: Potential therapeutic role of PD-L1 inhibitors.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare genetic disorder caused by defective nucleotide excision repair, leading to extreme UV sensitivity and early-onset skin cancers. Although PD-1/PD-L1 inhibitors have shown benefit in XP-associated tumors, the mechanisms that underpins these therapeutic responses remains unclear.

OBJECTIVE: To elucidate the molecular basis of XP pathogenesis in a 4-year-old Filipino girl and to investigate the potential role of PD-L1 inhibitors in treating XP-associated squamous cell carcinoma (SCC).

METHODS: A 4-year-old girl with XP underwent germline whole-exome sequencing. Transcriptomic profiling and immunochemistry validation were performed on XP-SCC and non-XP SCC tissues. In vitro assays using HaCaT keratinocytes evaluated DNA damage and PD-L1 expression following XPA knockdown and UV radiation. A Jurkat-HaCaT co-culture system, incorporating a PD-L1 neutralizing antibody, assessed T-cell attachment.

RESULTS: A homozygous splice-site variant in XPA (c.556-1 C>G) was identified. RNA-seq revealed marked up-regulation of CD274 (PD-L1), PDCD1 (PD-1), and STAT1 in XP-SCC. In vitro, XPA-deficient keratinocytes exhibited increased UV-induced DNA damage and synergistic PD-L1 induction. Jurkat T-cell attachment was elevated in UV-exposed, XPA-deficient groups; crucially, this enhanced attachment was significantly abolished by PD-L1 blockade.

CONCLUSION: XPA deficiency and UV-induced stress jointly enhance PD-L1 expression in XP-associated cSCC. These molecular and functional data provide biologic rationale for PD-L1-targeted therapy in XP and support further evaluation of immune checkpoint inhibitors in this population.