Improving the immunogenicity of dendritic cell-derived exosome-based vaccines for the immunotherapy of melanoma

Dendritic cell (DC)-derived exosomes (Dexo) are promising vaccine candidates for the treatment of cancer. We aimed at identifying a Dexo formulation with stronger immune stimulatory properties and efficacy as compared to the Dexo vaccines previously tested in pre-clinical and clinical settings of cancer immunotherapy. We therefore produced Dexo from DCs loaded with specific antigens and matured with the Toll-like receptor (TLR)-3 ligand poly(I:C) as danger signal. In vivo , Dexo produced from DCs loaded with OVA and stimulated with poly(I:C) could induce efficient activation of endogenous OVA-specific CD4 + and CD8 + T cells, leading to pro-inflammatory Th1 immune responses. We subsequently produced Dexo from DCs matured with poly(I:C) and cultured in the presence of oxidized B16F10 cell lysates (Dexo(B16+pIC)) as a source of B16F10 antigens. Mice bearing subcutaneous B16F10 tumors were vaccinated intradermally to target tumor-draining lymph nodes (tdLN), resulting in reduced tumor growth, limited metastasis burden and, most importantly, in prolonged survival of the mice vaccinated with Dexo(B16+pIC). Such benefits were associated with increased frequencies of effector CD8 + T cells in the tdLNs, spleen and tumor masses, reduced frequencies of tumor-infiltrating exhausted PD-1 + CD8 + T cells and increased frequencies of tumor-infiltrating NK and NK-T cells obtained upon vaccination with Dexo(B16+pIC) as compared to Dexo(B16), which instead are devoid of poly(I:C) and resemble the Dexo vaccines previously tested in human patients. Our results demonstrate that poly(I:C) is a promising candidate for the production of Dexo vaccines with improved immune stimulatory properties suitable for the immunotherapy of cancer.