Understanding the biology of antigen cross-presentation for the design of vaccines against cancer

Abstract

Antigen cross-presentation, the process in which exogenous antigens are presented on MHC class I molecules, is crucial for the generation of effector CD8(+) T cell responses. Although multiple cell types are being described to be able to cross-present antigens, in vivo this task is mainly carried out by certain subsets of dendritic cells (DCs). Aspects such as the internalization route, the pathway of endocytic trafficking, and the simultaneous activation through pattern-recognition receptors have a determining influence in how antigens are handled for cross-presentation by DCs. In this review, we will summarize new insights in factors that affect antigen cross-presentation of human DC subsets, and we will discuss the possibilities to exploit antigen cross-presentation for immunotherapy against cancer.

Keywords: CD8+ T cells; anti-cancer vaccine; antigen processing and presentation; cross-presentation; dendritic cells.

Figure 1

Molecular pathways leading to cross-presentation in DCs. DCs take up Ag by three general mechanisms, receptor-mediated endocytosis, phagocytosis, or macropinocytosis. Once the Ag reaches the endolysosomal pathway, depending of the specific routing, it may be degraded by the concourse of the mild pH and different types of cathepsins and other proteases. At this point, properly degraded Ag can be directly loaded into recycling MHC-I in the phagosome (Vacuolar pathway). Ag that still needs further processing must be transported to the cytosol (Cytosolic pathway) where it is degraded, together with endogenous proteins and DRiPs, by the proteasome. The peptides generated by the proteasome are transported by TAP or a yet uncharacterized transporter into the ER where they are loaded into MHC-I with the help of the peptide-loading complex. Further trimming in the ER prior to loading, it is possible by the presence of ER-localized endopeptidases (ERAP1 and 2). R, ribosome; CNX, calnexin; CRT, calreticulin; b2m, b2microglobulin; UGT1, UDP-glucose:glycoprotein glucosyltransferase 1; ERAP1/2, ER-aminopeptidases 1/2; PLC, peptide-loading complex; ERp57, protein disulfide isomerase 3; TAP1/2, transporter associated with antigen-presenting 1/2; DRiPs, defective ribosomal products; ROS, reactive oxygen species; NOX2, NADPH oxidase 2; CLR, C-type lectins; FcR, Fc receptors; SR, scavenger receptors.

Figure 2

Immunotherapeutic strategies to enhance anti-tumor immunity. Generation of a large pool of effector TA-specific T cells is induced by the intradermal injection of anti-tumor vaccines. Targeting of the vaccine to a particular skin DC subset is facilitated by modification with specific glycans that bind either to DC-SIGN or Langerin. Subsequent vaccine internalization induces presentation of TA-Ag and maturation of the DCs. Matured DCs migrate to draining lymph nodes to prime TA-specific CD8⁺ T cells and CD4⁺ T helper cells, leading to a large pool of cytotoxic effector T cells that are capable to infiltrate the tumor lesion and lyse tumor cells. Priming of TA-specific T cells may be enhanced by inclusion of immunostimulators such as GM-CSF and IL-21 in the DC-targeting vaccine. Systemic or intra-tumoral administered check-point inhibitors, such as anti-PD-1 and anti-CTLA-4, release the break on the anti-tumor immune response by limiting the activity of suppressive Treg and alleviate the priming and/or function of TA-specific CTLs. Similarly, anti-tumor immunity may be enhanced by manipulation of the local micromilieu via administration of DC activating antibodies (e.g., anti-CD40) or of TLR ligands that act directly on the tumor cells. It is anticipated that these strategies may enhance the efficacy of DC-targeted vaccination. Tc, cytotoxic CD8⁺ T cell; Th, T helper cell.