Intradermal DNA vaccination generates skin-resident memory CD8 T cells with enhanced antitumor properties
Felipe Gálvez-Cancino1#, Ernesto Lopez1#, Camila Flores1, Evelyn Menares1, Sebastián Cruz1, Sofía Hidalgo1, Eduardo Durán1, César Oyarce1, Alvaro Lladser1*
1Laboratory of Gene Immunotherapy, Fundación Ciencia & Vida, Santiago, Chile
#These authors contributed equally to this work
Intradermal vaccination efficiently induces long-lasting antigen-specific cytotoxic CD8 T cell responses due to the abundance of highly specialized dendritic cells in the skin. However, the ability of intradermal vaccination to generate skin-resident memory CD8 T cells remains poorly characterized. Here we show that intradermal vaccination with a DNA vaccine encoding the model antigen ovalbumin generates OVA(257-264)-specific CD8 T cell memory precursors (KLRG1-CD127+) expressing high levels of skin homing molecules E– and P–selectin ligands (ESL and PSL), as well as CXCR3. At the memory phase of the response, in addition to central- and effector-memory CD8 T cells found in lymphoid organs, antigen-specific memory CD8 T cells displaying a CD103+CD69+ phenotype accumulated in both vaccinated and non-vaccinated skin. Also, a population of antigen-specific CD103-CD69+ memory CD8 T cells was detected mainly in vaccinated skin. Intravascular staining allowed us to demonstrate that CD103+CD69+ CD8 T cells corresponded to truly resident memory T (TRM) cells. This was further corroborated by in vivo depletion experiments using anti-CD8 monoclonal antibodies, which resulted in the elimination of CD8 T cells from lymphoid organs and blood, as well as CD103-CD69+ CD8 T cells from skin. Remarkably, antigen-specific CD8 TRM cells were resistant to antibody-mediated in vivo depletion and completely suppressed the growth of intradermally injected ovalbumin-expressing B16F10 melanoma tumors. This work highlights the potential role of TRM cells in antitumor immunity and the use of intradermal vaccination against malignancies and infections of the skin.
CONICYT PFB-16, CORFO-INNOVA 12IDL2-13348, CONICYT fellowship (to FGC, EL, SC).