STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer
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Dinesh Chandra1, Wilber Quispe-Tintaya1, Arthee Jahangir1
1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;
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.
Insights
Cyclic diguanylate (c-di-GMP) enhances cancer vaccines by overcoming tumor immune suppression. This approach, targeting myeloid-derived suppressor cells and tumor cells, significantly reduced metastatic breast cancer in mice.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Metastatic cancer presents a significant therapeutic challenge due to immune suppression within the tumor microenvironment.
- Cancer vaccination holds promise for prevention and treatment but is hindered by immunosuppressive factors.
Purpose of the Study:
- To investigate if cyclic diguanylate (c-di-GMP), a STING agonist, can overcome immune suppression and enhance anti-metastatic breast cancer vaccination.
- To elucidate the mechanisms by which c-di-GMP impacts immune cells and tumor cells in the context of cancer immunotherapy.
Main Methods:
- Therapeutic immunization of mice with metastatic breast cancer (4T1 model) using a Listeria monocytogenes-based vaccine expressing Mage-b (LM-Mb).
- Administration of low-dose c-di-GMP (0.2 μmol/L) post-vaccination, and testing of high-dose c-di-GMP (3 mmol/L) followed by low-dose c-di-GMP.
- Analysis of immune cell populations (MDSCs), cytokine production (IL-12), T-cell responses (CD8 T-cells), and tumor cell apoptosis (caspase-3 activation).
Main Results:
- Combination therapy with LM-Mb vaccine and low-dose c-di-GMP led to near elimination of metastases.
- Low-dose c-di-GMP increased IL-12 production by myeloid-derived suppressor cells (MDSCs), enhancing T-cell responses to tumor antigens.
- High-dose c-di-GMP directly induced apoptosis in 4T1 tumor cells via caspase-3 activation.
- A regimen of high-dose followed by low-dose c-di-GMP showed efficacy comparable to the vaccine plus low-dose c-di-GMP, mediated by improved CD8 T-cell responses.
Conclusions:
- Cyclic diguanylate (c-di-GMP) effectively overcomes tumor-induced immune suppression, enhancing anti-cancer vaccine efficacy.
- Dual targeting of immune cells and tumor cells by c-di-GMP, through STING-dependent pathways, represents a promising strategy for metastatic breast cancer immunotherapy.
- Activation of STING pathways by c-di-GMP holds significant potential for advancing cancer immunotherapy.
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