741 UV-induced CD39 expression on immunosuppressive memory T cells in human cutaneous squamous cell carcinoma

Abstract

UV radiation and immunosuppression are two major risk factors for cutaneous squamous cell carcinoma (cSCC). Previous studies support a role for regulatory T cells in the pathogenesis of cSCC. We have shown that purinergic signaling plays a role in DNA damage repair (DDR). To investigate whether immunosuppressive T cells function to suppress DDR via purinergic signaling, we queried the expression of CD39 within human cSCC. CD39 catalyzes the conversion of extracellular ATP to ADP, leading to elevated extracellular AMP and adenosine (ADO) levels. We found that CD39 expression is increased on Tregs within human cSCCs when compared to T cells isolated from blood or non-lesional skin (p<0.05). Accordingly, the concentrations of extracellular ADP, AMP, and ADO are increased in tumors compared to normal skin (p<0.05). We find that increased ADO downregulates the expression of nucleosome assembly protein, an important component of DDR. We then examined the role of IL27, a proposed mediator of CD39 expression. Using a murine IL27 receptor KO model, we show that UV-induced CD39 expression is IL27-dependent and IL27 expression blocks UV-induced DDR in an in vitro keratinocyte model. In a mouse model of UV-induced cSCCs, inhibition of CD39 with POM1 limits early tumor growth. Interestingly, CD39 expression is significantly higher in human cSCCs that metastasize compared to those that are non-metastatic (p<0.01). Together, these data suggest a role for IL27-mediated CD39 upregulation on Tregs to mitigate effective DDR, promoting carcinogenesis and metastasis. This serves to further elucidate the mechanisms by which the immune system regulates carcinogenesis and provides several potential targets for therapeutic advancements.