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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.

SUBMITTER: Yao Y

PROVIDER: S-EPMC8345209 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Extracellular vesicles (EVs), particularly exosomes (30-150 nm), are an emerging delivery system in mediating cellular communications, which have been observed for priming immune responses by presenting parent cell signaling proteins or tumor antigens to immune cells. Therefore, preparation of antigenic exosomes that can play therapeutic roles, particularly in cancer immunotherapy, is emerging. However, standard benchtop methods (e.g., ultracentrifugation and filtration) lack the ability to purify antigenic exosomes specifically among other microvesicle subtypes, due to the non-selective and time-consuming (>10 h) isolation protocols. Exosome engineering approaches, such as the transfection of parent cells, also suffer from poor yields, low purity, and time-consuming operations. In this paper, we introduce a streamlined microfluidic cell culture platform for integration of harvesting, antigenic modification, and photo-release of surface engineered exosomes in one workflow, which enables the production of intact, MHC peptide surface engineered exosomes for cytolysis activation. A PDMS microfluidic cell culture chip is simply cast from a 3D-printed mold. This proof-of-concept study demonstrated the enhanced ability of harvested exosomes in antigen presentation and T cell activation, by decorating melanoma tumor peptides on the exosome surface (e.g., gp-100, MART-1, and MAGE-A3). Such surface engineered antigenic exosomes were harvested in real-time from the on-chip culture of leukocytes isolated from human blood, leading to much faster cellular uptake. The activation of gp100-specific CD8 T cells which were purified from the spleen of 2 Pmel1 transgenic mice was evaluated using surface engineered exosomes prepared from murine antigen presenting cells. Antigen-specific CD8 T cell proliferation was significantly induced by the engineered exosomes compared to that by native, non-engineered exosomes. This microfluidic platform serves as an automated and highly integrated cell culture device for rapid and real-time production of therapeutic exosomes that could advance cancer immunotherapy.

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DC-Derived Exosomes for Cancer Immunotherapy.

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