Dendritic cells (DCs) are highly efficient specialized antigen-presenting cells and have been regarded as promising targets in cancer immunotherapy. Cross-presentation of antigen by a subset of DCs, the CD8α-type DCs to CD8+ T cells is a fundamentally important mechanism in the defense against pathogens and tumors. In human and mice, CD8α-type DCs that are able to cross present uniquely express the chemokine receptor Xcr1 that binds the Xcl1 chemokine. We targeted antigens to cross- presenting CD8α-type DCs using Xcl1 inserted in dimeric vaccine molecules. Bivalent Xcl1 fusion vaccines bind specifically to and chemoattract CD8α-type DCs in a Xcr1 dependent manner.
With its easy accessibility and rich network of DCs, the skin appeals as a promising target site for vaccination. Using the PLEASE® laser microporation system, we specifically applied Xcl1 fusion vaccines into the murine dermis and targeted the cross-presenting CD8α-type dermal DCs. A single application of Xcl1 coupled to the modelantigen Ovalbumin (OVA) on the dermis of the mouse ear skin produced enhanced CD4 and CD8 T-cell responses, even in the absence of adjuvants. The first T-cell response was limited to the ear draining lymph node. This suggests that the application of antigens by laser microporation to the ear leads to a first localized immune response and thus limiting the possible amount of systemic side effects. However, such targeting of Xcl1-OVA also produced a striking enhancement of antibody responses. When the mice were challenged with B16 melanoma expressing OVA, treatment with the Xcl1-OVA could prevent development or mediate eradication of subcutaneous solid B16-OVA melanoma.
We conclude that targeting of dimeric fusion vaccine molecules to dermal CD8α-type DCs by use of Xcl1 represents a novel and promising method for inducing cytotoxic T cell reponses. Targeting the right dendritic cell subset in the right cutaneous compartment via PLEASE® laser microporation is a promising approach for immunotherapy also e.g. against allergies and pathogens.
Citation Format: Dorothea Terhorst, Dorothea Terhorst, Even Fossum, Bjarne Bogen, Sandrine Henri, Bernard Malissen. Laser-assisted intradermal delivery of Xcl1-specific fusion vaccines induces potent antitumor response. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A54.