Deletion of p53-Related Protein Kinase Suppresses Solar UV-Induced Photocarcinogenesis by Inhibiting PD-L1 Expression and Enhancing CD8 T-Cell Infiltration.

Abstract

Nonmelanoma skin cancers are primarily caused by solar UV exposure and represent the most common cancers in the United States. PRPK (p53-related protein kinase) is a protein kinase that is involved in multiple cancers, including colon cancer, myeloma, and hepatocellular carcinoma. In this study, we generated epidermal-specific PRPK-knockout mice using CRISPR/Cas9 technology in SKH1 hairless mice with loxP-flanked PRPK alleles, crossed with keratin 14-Cre (K14.Cre) mice. Our findings reveal that epidermal-specific deletion of PRPK significantly suppresses tumor growth in solar-simulated light-induced nonmelanoma skin cancer. Knocking down PRPK significantly suppresses cutaneous squamous cell carcinoma cell growth by inducing G1 phase arrest and promoting apoptosis. Mechanistically, PRPK deletion inhibits proliferating cell nuclear antigen and PD-L1 expression as well as the expression of transcription factors c-Myc, c-Jun, NF-κB, and activator protein-1, which mediate PD-L1 expression. Using a 3-dimensional culture system, we further demonstrate that PRPK deletion suppresses cutaneous squamous cell carcinoma cell growth. Flow cytometry analysis indicates that PRPK deletion enhances CD8 T-cell infiltration. This is accompanied by significant reductions in IL-6, MIP-2, and VEGF levels, reprogramming the tumor microenvironment to support CD8 T-cell infiltration. In summary, our study demonstrates that PRPK deletion suppresses solar UV-induced photocarcinogenesis by inhibiting PD-L1 expression and enhancing CD8 T-cell infiltration, highlighting its potential as a therapeutic target for nonmelanoma skin cancer.