title: STING ligand c-di-GMP improves cancer vaccination against metastatic breast cancer.
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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Dinesh
authors.initials: D
authors.lastname: Chandra
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Wilber
authors.initials: W
authors.lastname: Quispe-Tintaya
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Arthee
authors.initials: A
authors.lastname: Jahangir
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Denise
authors.initials: D
authors.lastname: Asafu-Adjei
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Ilyssa
authors.initials: I
authors.lastname: Ramos
authors.affiliation: Program in Oncology, University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore; Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland; and.
authors.forename: Herman O
authors.initials: HO
authors.lastname: Sintim
authors.affiliation: Program in Oncology, University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore; Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland; and.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Applied Chemistry, Aichi Institute of Technology, Toyota, Aichi, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Karagen Pharmaceuticals, Frederick;
authors.forename: David K R
authors.initials: DK
authors.lastname: Karaolis
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; claudia.gravekamp@einstein.yu.edu.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gravekamp
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D001943:Breast Neoplasms / Q000556:secondary* / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D045142:Cross-Priming; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy; D008089:Listeria monocytogenes / Q000235:genetics; D008325:Mammary Neoplasms, Experimental; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D059016:Tumor Microenvironment; D014613:Vaccines, Attenuated / Q000627:therapeutic use; D000099197:STING Protein
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006152:Cyclic GMP; D008565:Membrane Proteins; D014613:Vaccines, Attenuated; C530855:Sting1 protein, mouse; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid