Abstract 725: Targeting the skin microenvironment for effective cancer vaccines

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Abstract Skin, the most accessible organ, harbors keratinocytes and immunocytes that contribute to both innate and adaptive immunity, rendering it an ideal anatomic target for immunization. Keratinocytes can drive skin inflammation by producing pro-inflammatory mediators that promote cutaneous immune responses. Thus, targeting accessible keratinocytes to express transgenic antigens and increase production of pro-inflammatory mediators is a salient and attractive approach to vaccination, but remains a critical challenge to achieve. Toward this goal, we evaluated the effects of transient overexpression of the stress response factor x-box binding protein 1 (XBP1) in keratinocytes on the skin microenvironment. In vitro, keratinocytes genetically engineered to overexpress XBP1 increased production of both co-transduced exogenous antigen and pro-inflammatory mediators. In vivo, overexpression of XBP1 and transgenic antigen in keratinocytes induced both protective and therapeutic antitumor immunity that was associated with enhanced cutaneous expression of pro-inflammatory mediators and co-delivered antigen, increased skin-infiltrating immunocytes including dendritic cells (DCs), and the induction of durable antigen-specific CD8+ T cells and skin-resident memory CD8+ T cells. Importantly, in human skin, correlative effects were observed: transient overexpression of XBP1 in skin triggered the expression of genes linked to a pro-immunogenic microenvironment, increased the expression of the co-delivered antigen, and promoted the activation and IFN-γ-producing T cell-stimulating function of skin DCs. These findings provide novel insights into the rational design of cancer vaccines with improved immunogenicity through strategic modulation of the skin microenvironment. Citation Format: Jack R. You, Rong Hao, Louis D. Falo, Guo Chen, Xingxing Hao, Cara Carey, Zhaoyang You, Louis D. Falo. Targeting the skin microenvironment for effective cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 725.