DC-Derived Exosomes for Cancer Immunotherapy

Abstract

As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy.

Plasmacytoid Dendritic Cells and Cancer Immunotherapy

“…DCs process exogenous antigens in endosomal compartments including multivesicular endosomes which can release small inert vesicles 30–150 nm in diameter called exosomes (DCexos) following fusing with plasma membrane [ 104 , 105 , 106 , 107 ]. DCexos contain proteins, metabolites and nucleic acids including miRNAs (microRNAs), and play significant roles in intercellular communications and material transfer of their cargo [ 104 , 107 ]. DCexos additionally express complexes of MHC class I/II-antigenic epitopes and co-stimulatory molecules, making them capable of priming antigen-specific CD8 T cells [ 108 , 109 , 110 , 111 ].…”

Increasing the Therapeutic Efficacy of Extracellular Vesicles From the Antigen-Specific Antibody and Light Chain Perspective

“…Abovementioned obstacles and concerns prompted researchers to search for safer alternatives that could efficiently replace the living cells for therapeutic purposes. Consequently, EVs released by these cells become considered main promising candidates for cell-free therapies ( Tang et al, 2015 ; Johnson et al, 2021 ; Wang et al, 2021 ; Yao et al, 2021 ).…”

“…Thus, stem cell-derived EVs cannot differentiate but can promote immune tolerance ( Wang et al, 2021 ), and tissue regeneration ( Johnson et al, 2021 ) instead of tumorigenesis ( Lukomska et al, 2019 ), since they do not carry full genomic DNA material. Moreover, EVs can carry and present antigens as do dendritic cells, but they are unable to switch their phenotype ( Yao et al, 2021 ). Finally, EVs can induce antigen-targeted cytotoxicity against cancer cells without the risk of cytokine release syndrome development ( Tang et al, 2015 ).…”

“…Along these lines, dendritic cell-derived EVs demonstrated low clinical efficacy as maintenance immunotherapy in patients bearing inoperable but not progressive non-small cell lung cancer ( Besse et al, 2016 ). This could be due to the fact that EVs were collected from immature dendritic cells and then administered to patients with advanced cancer that likely had impaired immunoreactivity ( Yao et al, 2021 ). This clearly shows that the immune status of patients in target group has to be taken into account while designing appropriate EV-based drug or vaccine.…”

“…Moreover, since aggregation was firstly proved for MHC class II-expressing EVs, the possible MHC-restriction of their activity has to be elucidated with regard to the possibilities to use EVs from allogeneic donors. On the other hand, one can speculate that autologous dendritic cell-derived EVs loaded in vitro with dedicated peptides in a direct or indirect manner ( Morse et al, 2005 ) could be considered optimal for aggregation to greatly enhance their vaccine-like activity for instance in cancer immunotherapy ( Yao et al, 2021 ).…”