STING Ligand c-di-GMP Improves Cancer Vaccination against Metastatic Breast Cancer
Open Access
- 1 September 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 2 (9), 901-910
- https://doi.org/10.1158/2326-6066.cir-13-0123
Abstract
Cancer vaccination may be our best and most benign option for preventing or treating metastatic cancer. However, breakthroughs are hampered by immune suppression in the tumor microenvironment. In this study, we analyzed whether cyclic diguanylate (c-di-GMP), a ligand for stimulator of interferon genes (STING), could overcome immune suppression and improve vaccination against metastatic breast cancer. Mice with metastatic breast cancer (4T1 model) were therapeutically immunized with an attenuated Listeria monocytogenes (LM)–based vaccine, expressing tumor-associated antigen Mage-b (LM-Mb), followed by multiple low doses of c-di-GMP (0.2 μmol/L). This treatment resulted in a striking and near elimination of all metastases. Experiments revealed that c-di-GMP targets myeloid-derived suppressor cells (MDSC) and tumor cells. Low doses of c-di-GMP significantly increased the production of IL12 by MDSCs, in correlation with improved T-cell responses to Mage-b, whereas a high dose of c-di-GMP (range, 0.3–3 mmol/L) activated caspase-3 in the 4T1 tumor cells and killed the tumor cells directly. On the basis of these results, we tested one administration of high-dose c-di-GMP (3 mmol/L) followed by repeated administrations of low-dose c-di-GMP (0.2 μmol/L) in the 4T1 model, and found equal efficacy compared with the combination of LM-Mb and c-di-GMP. This finding correlated with a mechanism of improved CD8 T-cell responses to tumor-associated antigens (TAA) Mage-b and Survivin, most likely through cross-presentation of these TAAs from c-di-GMP–killed 4T1 tumor cells, and through c-di-GMP–activated TAA-specific T cells. Our results demonstrate that activation of STING-dependent pathways by c-di-GMP is highly attractive for cancer immunotherapy. Cancer Immunol Res; 2(9); 901–10. ©2014 AACR.Keywords
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This publication has 36 references indexed in Scilit:
- Nontoxic radioactive Listeria at is a highly effective therapy against metastatic pancreatic cancerProceedings of the National Academy of Sciences of the United States of America, 2013
- STING is a direct innate immune sensor of cyclic di-GMPNature, 2011
- Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cellsThe Journal of Experimental Medicine, 2011
- Vaccination with Mage-b DNA induces CD8 T-cell responses at young but not old age in mice with metastatic breast cancerBritish Journal of Cancer, 2009
- High Efficacy of a Listeria-Based Vaccine against Metastatic Breast Cancer Reveals a Dual Mode of ActionCancer Research, 2009
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- STING is an endoplasmic reticulum adaptor that facilitates innate immune signallingNature, 2008
- Mage-b vaccine delivered by recombinant Listeria monocytogenes is highly effective against breast cancer metastasesBritish Journal of Cancer, 2008
- Cyclic Di-GMP Stimulates Protective Innate Immunity in Bacterial PneumoniaInfection and Immunity, 2007
- Tregs and rethinking cancer immunotherapyJCI Insight, 2007