Targeting Cross-Presentation as a Route to Improve the Efficiency of Peptide-Based Cancer Vaccines

Abstract

Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1+ cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.

Straight to the point: targeted mRNA-delivery to immune cells for improved vaccine design

“…It is selectively expressed on cDC1 ( 170 ). Being a specific ligand, vaccines using XCL1 as targeting ligands fused to antigens (rather than monoclonal antibodies) have been developed and showed improved efficacy ( 171 , 172 ). An important communication from Fossum et al.…”

The CIt protocol: A blueprint to potentiate the immunogenicity of immunoproteasome-reprogrammed mesenchymal stromal cells

“…Despite significant improvements, clinical responses to DC vaccines remain largely frail due to hurdles related to insufficient antigen cross-presentation, impaired migratory capacity, and/or weak cytokine release. 42 , 43 , 44 , 45 , 46 , 47 , 48 With these limitations in perspective, we engineered IRMs, a type of non-hematopoietic APCs capable of surpassing DCs at mounting potent anti-tumoral responses against both murine T-cell lymphoma and melanoma caused by EG.7 and B16 cells, respectively. 11 Although exhibiting impressive potencies in pre-clinical models, the IRM vaccination protocol used so far is logistically impractical.…”

Precision-engineering of subunit vaccine particles for prevention of infectious diseases

“…The ability of DCs to present extracellular antigens in the context of MHC class I, a phenomenon called cross-presentation, can be an ideal target for the targeted delivery of vaccine antigens (20). Adjuvants such as MF59 and QS-21 in combination with TLR ligands can facilitate cytosolic or vacuole pathways of cross-presentation (91).…”

“…CPPs are comprised of 6 to 30 amino acid residues and majority of them are basic amino acid residues, leading to an overall positive net charge (92-94). Recently the use of arginine-and lysine-rich CPPs in conjunction with particulate vaccines promotes the MHC class I pathway cross-presentation effectively against viral and tumor antigens (20,92,93). Moreover, DC targeting peptides (DCpep) are strongly targeted to DCs.…”

“…MHC class I and II pathways are usually involved presenting peptides from intracellular or extracellular pathogens, respectively. However, dendritic cells (DCs) possess the ability to divert peptides derived from extracellular pathogens to cytotoxic CD8 + T cells via the MHC class I presentation pathway (20). A phagosome is a key organelle in antigen cross-presentation which primarily induces cytotoxic CD8 + T cell responses.…”