Exploring the in vivo mechanism of cytotoxic T cell generation following a prime and boost with a peptide vaccine and poly-ICLC adjuvant, Sultan et al. found that dendritic cells are essential not only for peptide processing and cross-presentation, but also for producing IFN-I, which induces IL-15 in an unidentified bone-marrow-derived cell type to promote CTL expansion. Although both poly-IC and poly-ICLC were sufficient for stimulating TLR3 in the endosomal compartment for production of IL-12, poly-ICLC could also stimulate MDA5 in the cytoplasm, inducing higher levels of IFN-I production.

Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical approach to treat cancer. We have previously described a peptide vaccination strategy that generates vast numbers of endogenous tumor-reactive CTLs after two sequential immunizations (prime-boost) using poly-ICLC adjuvant, which stimulates endosomal toll-like receptor 3 (TLR3) and cytoplasmic melanoma differentiation antigen 5 (MDA5). Dendritic cells (DCs) play an important role not only in antigen presentation but are critical in generating costimulatory cytokines that promote CTL expansion. Poly-ICLC was shown to be more effective than poly-IC in generating type-I interferon (IFN-I) in various DC subsets, through its enhanced ability to escape the endosomal compartment and stimulate MDA5. In our system, IFN-I did not directly function as a T cell costimulatory cytokine, but enhanced CTL expansion through the induction of IL15. With palmitoylated peptide vaccines, CD8alpha+ DCs were essential for peptide crosspresentation. For vaccine boosts, non-professional antigen-presenting cells were able to present minimal epitope peptides, but DCs were still required for CTL expansions through the production of IFN-I mediated by poly-ICLC. Overall, these results clarify the roles of DCs, TLR3, MDA5, IFN-I and IL15 in the generation of vast and effective antitumor CTL responses using peptide and poly-IC vaccines.

Author Info: (1) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4121, Augusta, GA, 30912, USA. (2) Cancer Immunology, Immunotherapy

Author Info: (1) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4121, Augusta, GA, 30912, USA. (2) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4121, Augusta, GA, 30912, USA. (3) Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan. (4) Oncovir, Inc., Washington, DC, USA. (5) Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4121, Augusta, GA, 30912, USA. ecelis@augusta.edu.

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