Cross-priming in cancer immunology and immunotherapy

Cytotoxic T cell immune responses against cancer crucially depend on the ability of a subtype of professional antigen-presenting cells termed conventional type 1 dendritic cells (cDC1s) to cross-present antigens. Cross-presentation comprises redirection of exogenous antigens taken from other cells to the major histocompatibility complex class I antigen-presenting machinery. In addition, once activated and having sensed viral moieties or T helper cell cooperation via CD40–CD40L interactions, cDC1s provide key co-stimulatory ligands and cytokines to mount and sustain CD8+ T cell immune responses. This regulated process of cognate T cell activation is termed cross-priming. In cancer mouse models, CD8+ T cell cross-priming by cDC1s is crucial for the efficacy of most, if not all, immunotherapy strategies. In patients with cancer, the presence and abundance of cDC1s in the tumour microenvironment is markedly associated with the level of T cell infiltration and responsiveness to immune checkpoint inhibitors. Therapeutic strategies to increase the numbers of cDC1s using FMS-like tyrosine kinase 3 ligand (FLT3L) and/or their activation status show evidence of efficacy in cancer mouse models and are currently being tested in initial clinical trials with promising results so far. In this Review, Luri-Rey et al. present evidence for the crucial role of conventional type 1 dendritic cells in cross-presenting antigens from other cells via the major histocompatibility complex class I antigen-presenting machinery, which in turn is necessary to prime CD8+ T cells, which then mount efficient immune responses against cancer. The authors also discuss how we can exploit these processes in cancer immunotherapy by increasing the number and/or maturation or activation status of this specialist subtype of antigen-presenting cell.