Abstract 3487: Mechanistic role of CD70 in UV exposed keratinocytes and cutaneous squamous cell carcinoma (cSCC)

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising due to limited prevention strategies. Significant gaps persist in understanding the mechanisms of UV-induced DNA damage and immune modulation in skin cancer development. By analyzing expression data from sun-exposed and sun-protected skin in the Genotype-Tissue Expression (GTEx) database and the Gene Expression Omnibus (GEO), we identified CD70 as a key gene linking solar UV exposure, immune responses, and photocarcinogenesis. Reverse Phase Protein Microarray Analysis (RPPA) revealed a significant upregulation of CD70 in sun-damaged skin compared to sun-protected skin. CD70 expression was also markedly higher in actinic keratosis (AK) and cSCC compared to normal tissue. In this study, we investigated the mechanistic role of CD70 in solar simulated light (SSL,149 kJ/m2 UVA & 7.2 kJ/m2 UVB)-exposed keratinocytes and cSCC. CD70 expression was found to increase in keratinocytes following SSL irradiation in a dose- and time-dependent manner. Deletion of CD70 effectively suppressed cSCC cell growth in both 2D and 3D culture models. RNA sequencing (RNA-seq) analysis (shCon vs. shCD70) revealed that CD70 regulates gene expression changes induced by solar UV exposure through multiple oncogenic pathways. CD70-associated genes are strongly linked to AK and cSCC and involve critical signaling pathways, including MAPK, Rap1, and others. Additionally, CD70 deletion inhibits NFkappa B nuclear translocation, as demonstrated by luciferase assays and immunofluorescence analysis. In summary, these findings underscore the pivotal role of CD70 in SSL-induced skin damage and photocarcinogenesis. The CD70 inhibition may offer a novel targeted strategy for preventing and treating cSCC. Citation Format: Asad Khan, Qiushi Wang, Chengcheng Hu, Emannuel Petricoin, Rebecca Morris, Georg T. Wondrak, Ann M. Bode, Clara Curiel-Lewandrowski, Tianshun Zhang. Mechanistic role of CD70 in UV exposed keratinocytes and cutaneous squamous cell carcinoma (cSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3487.