Role of MDA5 and interferon-I in dendritic cells for T cell expansion by anti-tumor peptide vaccines in mice

Cancer Immunol Immunother. 2018 Jul;67(7):1091-1103. doi: 10.1007/s00262-018-2164-6. Epub 2018 Apr 25.


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, CD8α+ 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.

Keywords: Dendritic cells; Interleukin-15; MDA5; Peptide vaccines; Poly-IC; Type-I interferon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer Vaccines / administration & dosage*
  • Carboxymethylcellulose Sodium / administration & dosage
  • Carboxymethylcellulose Sodium / analogs & derivatives
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Interferon Inducers / administration & dosage
  • Interferon Type I / metabolism*
  • Interferon-Induced Helicase, IFIH1 / physiology*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C / administration & dosage
  • Polylysine / administration & dosage
  • Polylysine / analogs & derivatives
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • Toll-Like Receptor 3 / physiology
  • Tumor Cells, Cultured
  • Vaccination
  • Vaccines, Subunit / administration & dosage*


  • Cancer Vaccines
  • Interferon Inducers
  • Interferon Type I
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Vaccines, Subunit
  • Polylysine
  • poly ICLC
  • Ifih1 protein, mouse
  • Interferon-Induced Helicase, IFIH1
  • Carboxymethylcellulose Sodium
  • Poly I-C