Targeting Immune Checkpoint VISTA reduces early skin interferon (IFN) and late pro-fibrotic responses following skin injury 2791

Description Antibodies suppressing the activity of the immune checkpoint VISTA to stimulate anti-tumor immune responses are in cancer clinical trials. Whether VISTA activating antibodies can be leveraged to suppress inflammatory responses and tissue injury is not well understood. VISTA deficient mice demonstrate higher type I and II IFN response after acute skin injury by ultraviolet B (UVB) light, compared to wild-type controls. Moreover, absence of VISTA results in visibly worse skin injury days after UV (higher injury score), accompanied by the expression of pro-fibrotic genes: Tgfb and Col1a1. To test if activating VISTA suppresses UV-induced IFN-I and pro-fibrotic responses, we treated UV-exposed mice expressing human VISTA (hVISTA) with anti-hVISTA IgG (803, GG8) or isotype control. Anti-hVISTA IgG suppressed early (3hr) expression of IFN stimulated genes, IFNk and IFNg, but not IFNa or IFNb, compared to isotype treated mice. On day 4 after UV anti-hVISTA IgG suppressed Tgfb and Col1a1 expression. Decreased IFN and pro-fibrotic responses in anti-VISTA treated group were accompanied by ∼50% decrease in skin injury score on day 2 after UV. Flow cytometry analysis revealed a reduction in activated macrophages and T cells, and an increase in the proportion of regulatory T cells. Moreover, activating VISTA reduced UV-induced apoptotic cells in the skin. In conclusion, VISTA activation may play a role in mitigating UV-induced skin sensitivity and fibrosis in lupus skin disease. Funding Sources 5R01AI148430-05 - VISTA is a negative checkpoint regulator of innate immunity Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)