ENTPD1(CD39) expression inhibits ultraviolet radiation-induced DNA damage repair via purinergic signaling and is associated with metastasis in human cutaneous squamous cell carcinoma.

Ultraviolet radiation (UVR) and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells (Tregs) promote cSCC carcinogenesis and in other solid tumors, infiltrating Tregs and CD8+ T cells express ENTPD1 (also known as CD39), an ecto-enzyme that catalyzes the rate-limiting step in converting extracellular ATP to extracellular adenosine. We previously demonstrated that extracellular purine nucleotides influence DNA Damage Repair (DDR). Here we investigate whether DDR is modulated via purinergic signaling in cSCC. We found increased ENTPD1 expression on T cells within cSCCs when compared to T cells from blood or non-lesional skin and accordingly, concentrations of derivative extracellular ADP, AMP, and adenosine are increased in tumors compared to normal skin. Importantly, ENTPD1 expression is significantly higher in human cSCCs that metastasize compared to those that are non-metastatic. We also identify in a mouse model that ENTPD1 expression is induced by UVR in an IL27-dependent manner. Finally, increased extracellular adenosine is shown to downregulate the expression of NAP1L2, a nucleosome assembly protein we show to be important for DDR secondary to UVR. Together, these data suggest a role for ENTPD1 expression on skin-resident T cells to regulate DDR via purinergic signaling to promote skin carcinogenesis and metastasis.