238 Effect of CXCL1-neutralizing antibodies on UV-induced skin tumors in mice deficient in DNA repair systems

Ultraviolet (UV)-induced DNA damage and skin inflammation are well-known mechanisms of carcinogenesis. However, the extent to which contributes UV-induced carcinogenesis is unknown. The xeroderma pigmentosum group A (XPA) model mice (Xpa-KO mice) deficient in repair systems, making them susceptible cancer. We previously reported that blood levels CXCL1, a neutrophil attractant chemokine, increases after UV irradiation, administration CXCL1-neutralizing monoclonal antibodies (CXCL1-mAb) suppresses Xpa-KO mice. Here, we investigated impact CXCL1-mAb on exposed UVB for 10 weeks. treatment delayed onset tumor development from 8 14 weeks, number tumors decreased 8.6 3.8 average at 15 Although RAS pathway mutations more common than PI3K carcinogenesis, whole exome sequencing four each two groups (CXCL1-mAb-treated non-treated) revealed treated had Akt Pik3ca but not Kras Hras. In contrast, non-treated Hras Pik3ca. CXCL1 CXCR2 ligand, CXCL1/CXCR2 axis known activate both signaling pathways. Our findings suggest inhibition shifts mutation spectrum presumably because activates efficiently pathway. Future research needed elucidate mechanism by facilitates