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

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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.

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Abbreviations

ACT:

Adoptive cell therapy

APC:

Antigen-presenting cell

Bt:

Boost

c-di-GMP:

Cyclic diguanylate monophosphate

DC:

Dendritic cell

ELISA:

Enzyme-linked immune assay

EliSpot:

Enzyme-linked immunospot

IFNαβR:

Interferon alpha–beta receptor

IFN-I:

Type-I interferon

IFNγ:

Interferon gamma

i.v.:

Intravenous

MDA5:

Melanoma differentiation-associated protein 5

Ova:

Ovalbumin

Pam:

Palmitic acid

Poly-IC:

Polyinosinic-polycytidylic acid

Pr:

Prime

PRR:

Pattern recognition receptor

STING:

Stimulator of interferon genes

TLR3:

Toll-like receptor 3

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Acknowledgments

This work was supported by grants from the National Cancer Institute of the National Institutes of Health, R01CA136828 and R01CA157303, and by start-up funds from Georgia Regents University Cancer Center and the Georgia Research Alliance (GRA). We thank Ms. Diane Addis for the valuable technical expertise provided to this project and the GRU Cancer Center Flow Cytometry Core for services provided.

Conflict of interest

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). Zili Wang declares no conflict of interest.

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  1. Zili Wang

    Present address: Chemotherapy Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China

Authors and Affiliations

  1. Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, CN-4121, 1410 Laney Walker Blvd, Augusta, GA, 30912, USA

    Zili Wang & Esteban Celis

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  1. Zili Wang
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  2. Esteban Celis
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Correspondence to Esteban Celis.

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Wang, Z., Celis, E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol Immunother 64, 1057–1066 (2015). https://doi.org/10.1007/s00262-015-1713-5

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  • DOI: https://doi.org/10.1007/s00262-015-1713-5

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