Dendritic cells present cancer-derived p:MHCI molecules to prime anti-tumor CD8 T cells

Abstract

Abstract Migratory CD103+ dendritic cells (DCs) initiate anti-tumor CD8+ T cell responses by presenting tumor antigens on class I major histocompatibility complex (MHCI) molecules. Given that CD103+ DCs are adept at cross-presenting antigens, the current paradigm is that they present tumor antigens via classical TAP-dependent cross-presentation. However, recent studies have shown that DCs can present cellular antigens by other means, including by acquiring and presenting intact peptide:MHC (p:MHC) complexes from other cells, a mechanism known as cross-dressing. To assess the role of antigen cross-dressing in priming spontaneous anti-tumor CD8+ T cell responses in vivo, the murine MHCI molecule H2-Kb was knocked out in B16 melanoma and C1498 leukemia cell lines. Engraftment of these syngeneic tumors expressing Kb-restricted model antigens into C57BL/6 mice revealed a defect in antigen-specific CD8+ T cell priming when the cancer cells lacked Kb. While the absence of Kb expression by the tumor did not alter the level of costimulatory molecules on DCs or the cytokine milieu of the draining lymph node, it was correlated with a reduction in p:MHCI molecules for a model tumor antigen, SIINFEKL, presented by CD103+ DCs. Further, tumor-derived GFP-tagged Kb molecules were readily observed on the surface of DCs isolated from the tumor, and the presentation of acquired tumor-derived p:MHCI complexes by migratory DCs from tumor-draining lymph nodes of Kb/Db−/− and Tap1−/− mice was sufficient for ex vivo CD8+ T cell priming. Together, these data address a critical knowledge gap in tumor antigen presentation, and highlight a previously under-appreciated pathway as a crucial and non-redundant mechanism of CD8+ T cell activation by DCs.