056 Systems approach to evaluate disease factors in pemphigus

Abstract

Skin is a uniquely accessible and responsive target for vaccine delivery. Emerging evidence suggests that keratinocytes can modulate skin immunity in response to diverse stimuli, producing either proinflammatory or immune suppressive mediators depending on the nature of the exogenous stress. To improve the immunogenicity of skin targeted vaccines, we engineered keratinocytes to support a proinflammatory local environment. Keratinocytes were genetically engineered to express the stress response transcription factor x-box binding protein 1 (XBP1). In a mouse model, keratinocyte-specific overexpression of XBP1 was transient and induced a proimmunogenic skin microenvironment characterized by increased expression of proinflammatory mediators, localized inflammatory infiltrates, including localized increases of dermal CD103 + DCs, XCR1 + DCs, plasmacytoid DCs, gd T cells, and group 1 innate lymphoid cells. Simultaneous non-viral delivery of plasmids driving expression of XBP1 and antigen OVA resulted in increased antigen expression and increased the induction of antigen-specific cellular and humoral responses, including durable antigen-specific skinresident memory CD8 T cells and efficacious protective immunity, compared to delivery of antigen encoding plasmid alone. This translated to increased titers of ZIKV-ENV antibody in a Zika virus model, and improved therapeutic immunity in a clinically reflective endogenous melanoma model. Further, overexpression of XBP1 in keratinocytes in human skin resulted in a proimmunogenic skin microenvironment. These findings support the feasibility of keratinocyte targeted DNA vaccines to induce a proinflammatory skin microenvironment for effective immunization.