title: STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice.
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.
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, CN-4121, 1410 Laney Walker Blvd, Augusta, GA, 30912, USA.
authors.forename: Zili
authors.initials: Z
authors.lastname: Wang
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007370:Interferon Type I / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008565:Membrane Proteins / Q000819:agonists; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000008:administration & dosage; D017471:Receptors, Interferon / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D022223:Vaccines, Subunit / Q000627:therapeutic use; D000099197:STING Protein
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D019496:Cancer Vaccines; D006152:Cyclic GMP; D018984:Epitopes, T-Lymphocyte; D007370:Interferon Type I; D008565:Membrane Proteins; D011070:Poly I-C; D017471:Receptors, Interferon; D022223:Vaccines, Subunit; C530855:Sting1 protein, mouse; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid