Dendritic cells can prime anti-tumor CD8+ T cell responses through major histocompatibility complex cross-dressing

Antigen cross-presentation, wherein dendritic cells (DCs) present exogenous antigen on major histocompatibility class I (MHC-I) molecules, is considered the primary mechanism by which DCs initiate tumor-specific CD8+ T cell responses. Here, we demonstrate that MHC-I cross-dressing, an antigen presentation pathway in which DCs acquire and display intact tumor-derived peptide:MHC-I molecules, is also important in orchestrating anti-tumor immunity. Cancer cell MHC-I expression was required for optimal CD8+ T cell activation in two subcutaneous tumor models. In vivo acquisition of tumor-derived peptide:MHC-I molecules by DCs was sufficient to induce antigen-specific CD8+ T cell priming. Transfer of tumor-derived human leukocyte antigen (HLA) molecules to myeloid cells was detected in vitro and in human tumor xenografts. In conclusion, MHC-I cross-dressing is crucial for anti-tumor CD8+ T cell priming by DCs. In addition to quantitatively enhancing tumor antigen presentation, MHC cross-dressing might also enable DCs to more faithfully and efficiently mirror the cancer cell peptidome. [Display omitted] •Optimal anti-tumor CD8+ T cell priming requires MHC-I expression on cancer cells•Tumor-resident DCs and macrophages dress with cancer cell MHC-I in vivo•MHC-I cross-dressing is sufficient for antigen-specific CD8+ T cell priming ex vivo•The impact of MHC-I cross-dressing on CD8+ T cell priming differs between tumor models Although antigen cross-presentation is important for DCs to orchestrate anti-tumor CD8+ T cell responses, the role of alternative antigen presentation pathways is unclear. MacNabb et al. show that CD8+ T cell priming can be mediated by DCs that acquire and present tumor-derived MHC-I complexes—a phenomenon known as MHC cross-dressing.