Role of MDA5 and interferon-I in dendritic cells for T cell expansion by anti-tumor peptide vaccines in mice
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.
KeywordsPeptide vaccines Poly-IC Dendritic cells MDA5 Type-I interferon Interleukin-15
Adoptive cell transfer
Cytotoxic T lymphocyte
Diphtheria toxin receptor
Type-I interferon receptor
IL-2 immune complex
Melanoma differentiation-associated protein 5
MHC class I
MHC class II
Non-professional antigen-presenting cell
Poly-IC stabilized with poly-lysine and carboxymethyl cellulose
Poly-IC stabilized with PEI
T cell receptor for antigen
Toll-like receptor 3
Tyrosinase-related protein 1
HS designed, performed experiments, analyzed the data and helped to write the manuscript. TK and JW performed experiments. Andres Salazar discussed the results and provided reagents. EC designed and analyzed the experiments, and wrote the manuscript.
This work was supported by National Cancer Institute grant R01CA157303, and by start-up funds from Augusta University, Georgia Cancer Center and the Georgia Research Alliance (GRA).
Compliance with ethical standards
Conflict of interest
A. Salazar is President and CEO of Oncovir, Inc. and is developing poly-ICLC (Hiltonol ™) for the clinic. Esteban Celis has filed patent applications based on the use of synthetic peptides and poly-IC combinatorial vaccines. The rights of the patent applications have been transferred to the Moffitt Cancer Center (Tampa, FL). Other authors declare no conflict of interest.
Statement on the welfare of animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in the experiments involving animals were in accordance with the ethical standards of the Augusta University Institutional Animal Care and Use Committee where all the studies were conducted (Protocol No. 2013 − 0598, approved on 11/21/2016).
This article does not contain any studies with humans done by any of the authors.
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