Abstract
Cross-presenting Xcr1+CD8α DCs are attractive APCs to target for therapeutic cancer vaccines, as they are able to take up and process antigen from dying tumor cells for their MHCI-restricted presentation to CD8 T cells. To this aim, we developed fusion proteins made of the Xcr1 ligand Xcl1 fused to an OVA synthetic long peptide (SLP) and IgG1 Fc fragment. We demonstrated the specific binding and uptake of the Xcl1 fusion proteins by Xcr1+ DCs. Most importantly, their potent adjuvant effect on the H-2Kb/OVA specific T cell response was associated with a sustained tumor control even against the poorly immunogenic B16-OVA melanoma tumor. The increased tumor protection correlated with higher tumor infiltration of antigen-specific CD8+ T cells, increased IFNγ production and degranulation potential. Altogether, these results demonstrate that therapeutic cancer vaccines may be greatly improved by the combination of SLP antigen and Xcl1 fusion proteins.
Highlights
One of the key requirements for successful therapeutic cancer vaccinations relies on the ability to target antigen to cross-presenting dendritic cells (DCs), a subtype of DCs which have the capacity to shunt a proportion of internalized antigens from the endosomal compartments to the cytosol, where they are processed for loading onto MHC class I molecules, resulting in efficient CD8+ T cell responses [1]
With the aim to optimize synthetic long peptide (SLP) vaccines by targeting the antigen to Xcr1+ cross-presenting DCs, a recombinant fusion protein was produced with the ovalbumin (OVA) SLP antigen fused to the Xcl1 chemokine, followed by the murine IgG1 Fc for stability, dimerization and purification purposes (Supplementary Figure 1)
CD11c+-enriched DCs from naïve WT and Batf3−/− mice were incubated with the Xcl1-(OVA SLP)Fc fusion proteins at 37◦C, and specific binding was detected with a fluorescently-labeled anti-IgG1-Fc antibody
Summary
One of the key requirements for successful therapeutic cancer vaccinations relies on the ability to target antigen to cross-presenting dendritic cells (DCs), a subtype of DCs which have the capacity to shunt a proportion of internalized antigens from the endosomal compartments to the cytosol, where they are processed for loading onto MHC class I molecules, resulting in efficient CD8+ T cell responses [1]. The chemokine receptor Xcr was shown to be the main marker characterizing murine [2] as well as human cross-presenting DCs [3,4,5], and their superior cross-presentation capacities of soluble and cell-associated antigens has been demonstrated in both mice [2, 6, 7] and humans [3, 8]. Xcr is expressed in ∼80% of lymphoid organ-resident CD8α+ DCs as well as in ∼80% of migratory dermal CD103+ DCs [6]. Xcr1-expressing DCs migrate toward the chemokine Xcl secreted by activated CTLs, NK and NKT cells involved in the cytotoxic response [3, 11]. In contrast to many chemokine ligands that bind to several receptors, Xcl binds exclusively to the Xcr receptor and is often co-secreted with Th1 profile cytokines, such as IFNγ, MIP-1α, MIP-1β, and RANTES by activated murine NK cells, Th1 cells, and CD8+ T lymphocytes [12]
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