Exosomal cancer immunotherapy is independent of MHC molecules on exosomes

Peptide-loaded exosomes are promising cancer treatment vehicles; however, moderate T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. Researchers from the Karolinska Institute previously demonstrated that antigen-loaded exosomes carry whole protein antigens and require B cells for inducing antigen-specific T cells. Therefore, they investigated the relative importance of exosomal major histocompatibility complex (MHC) class I for the induction of antigen-specific T cell responses and tumour protection. The researchers show that ovalbumin-loaded dendritic cell-derived exosomes from MHCI-/- mice induce antigen-specific T cells at the same magnitude as wild type exosomes. Furthermore, exosomes lacking MHC class I, as well as exosomes with both MHC class I and II mismatch, induced tumour infiltrating T cells and increased overall survival to the same extent as syngeneic exosomes in B16 melanoma. In conclusion, T cell responses are independent of exosomal MHC/peptide complexes if whole antigen is present. This establishes the prospective of using impersonalised exosomes, and will greatly increase the feasibility of designing exosome-based vaccines or therapeutic approaches in humans.

Possible mechanisms for T cell stimulation by antigen-loaded exosomes

Dendritic cell-derived exosomes carry MHC class I and II molecules on the surface and A. can stimulate T cells directly by binding to the T cell receptor. Direct stimulation of T cells requires syngeneic MHC (black) molecules on exosomes due to MHC restriction. B. Uptake of exosomes by antigen presenting cells can lead to their degradation and loading of exosomal peptides on the APC´s MHC molecules or C. the whole exosomal MHC/peptide complex (green) can be recycled and exposed on the cell surface.