STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice

Cancer Immunol Immunother. 2015 Aug;64(8):1057-66. doi: 10.1007/s00262-015-1713-5. Epub 2015 May 19.

Abstract

Therapeutic vaccines to induce anti-tumor CD8 T cells have been used in clinical trials for advanced melanoma patients, but the clinical response rate and overall survival time have not improved much. We believe that these dismal outcomes are caused by inadequate number of antigen-specific CD8 T cells generated by most vaccines. In contrast, huge CD8 T cell responses readily occur during acute viral infections. High levels of type-I interferon (IFN-I) are produced during these infections, and this cytokine not only exhibits anti-viral activity but also promotes CD8 T cell responses. The studies described here were performed to determine whether promoting the production of IFN-I could enhance the potency of a peptide vaccine. We report that cyclic diguanylate monophosphate (c-di-GMP), which activates the stimulator of interferon genes, potentiated the immunogenicity and anti-tumor effects of a peptide vaccine against mouse B16 melanoma. The synergistic effects of c-di-GMP required co-administration of costimulatory anti-CD40 antibody, the adjuvant poly-IC, and were mediated in part by IFN-I. These findings demonstrate that peptides representing CD8 T cell epitopes can be effective inducers of large CD8 T cell responses in vaccination strategies that mimic acute viral infections.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • CD40 Antigens / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / therapeutic use*
  • Cyclic GMP / administration & dosage
  • Cyclic GMP / adverse effects
  • Cyclic GMP / analogs & derivatives*
  • Epitopes, T-Lymphocyte / administration & dosage
  • Humans
  • Immunotherapy / methods*
  • Interferon Type I / immunology
  • Lymphocyte Activation / drug effects
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy*
  • Membrane Proteins / agonists
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C / administration & dosage
  • Receptors, Interferon / genetics
  • Skin Neoplasms / immunology
  • Skin Neoplasms / therapy*
  • Vaccines, Subunit / therapeutic use

Substances

  • Antibodies, Monoclonal
  • CD40 Antigens
  • Cancer Vaccines
  • Epitopes, T-Lymphocyte
  • Interferon Type I
  • Membrane Proteins
  • Receptors, Interferon
  • Sting1 protein, mouse
  • Vaccines, Subunit
  • bis(3',5')-cyclic diguanylic acid
  • Cyclic GMP
  • Poly I-C