TY - JOUR
T1 - CD11c-targeted delivery of DNA to dendritic cells leads to cGAS- and STING-dependent maturation
AU - Laursen, Marlene Fyrstenberg
AU - Christensen, Esben
AU - Degn, Laura L. T.
AU - Jønsson, Kasper
AU - Jakobsen, Martin R.
AU - Agger, Ralf
AU - Kofod-Olsen, Emil
PY - 2018
Y1 - 2018
N2 - Immunotherapeutic activation of tumor-specific T cells has proven to be an interesting approach in anticancer treatment. Particularly, anti-CTLA-4 and anti-PD-1/PD-L1 treatment looks promising, and conceivably, even better clinical results might be obtained if such treatment could be combined with boosting the existing tumor-specific T-cell response. One way to achieve this could be by increasing the level of maturation of dendritic cells locally and in the draining lymph nodes. When exposed to cancer cells, dendritic cells may spontaneously mature because of danger-associated molecular patterns derived from the tumor cells. Double-stranded DNA play a particularly important role in the activation of the dendritic cells, through engagement of intracellular DNA-sensors, and signaling through the adaptor protein STING. In the present study, we have investigated the maturational response of human monocyte-derived dendritic cells (moDC) and human monocytic THP-1 cells to targeted and untargeted DNA. We used an anti-CD11c antibody conjugated with double-stranded DNA to analyze the maturation status of human moDCs, as well as maturation using a cGAS KO and STING KO THP-1 cell maturation model. We found that dendritic cells can mature after exposure to cytoplasmic double-stranded DNA delivered through CD11c-mediated endocytosis. Moreover, we show that THP-1 cells matured using IL-4, GM-CSF, and ionomycin upregulate DC-maturation markers after CD11c-targeted delivery of double-stranded DNA. This upregulation is completely abrogated in cGAS KO and STING KO cells.
AB - Immunotherapeutic activation of tumor-specific T cells has proven to be an interesting approach in anticancer treatment. Particularly, anti-CTLA-4 and anti-PD-1/PD-L1 treatment looks promising, and conceivably, even better clinical results might be obtained if such treatment could be combined with boosting the existing tumor-specific T-cell response. One way to achieve this could be by increasing the level of maturation of dendritic cells locally and in the draining lymph nodes. When exposed to cancer cells, dendritic cells may spontaneously mature because of danger-associated molecular patterns derived from the tumor cells. Double-stranded DNA play a particularly important role in the activation of the dendritic cells, through engagement of intracellular DNA-sensors, and signaling through the adaptor protein STING. In the present study, we have investigated the maturational response of human monocyte-derived dendritic cells (moDC) and human monocytic THP-1 cells to targeted and untargeted DNA. We used an anti-CD11c antibody conjugated with double-stranded DNA to analyze the maturation status of human moDCs, as well as maturation using a cGAS KO and STING KO THP-1 cell maturation model. We found that dendritic cells can mature after exposure to cytoplasmic double-stranded DNA delivered through CD11c-mediated endocytosis. Moreover, we show that THP-1 cells matured using IL-4, GM-CSF, and ionomycin upregulate DC-maturation markers after CD11c-targeted delivery of double-stranded DNA. This upregulation is completely abrogated in cGAS KO and STING KO cells.
KW - Journal Article
KW - DC maturation
KW - cGAS
KW - Antibody-Targeting
KW - STING
KW - CD11c Antigen/metabolism
KW - Nucleotidyltransferases/genetics
KW - Programmed Cell Death 1 Receptor/immunology
KW - Immunotherapy/methods
KW - Humans
KW - RNA, Small Interfering/genetics
KW - Membrane Proteins/genetics
KW - THP-1 Cells
KW - Antibodies, Monoclonal/therapeutic use
KW - Dendritic Cells/physiology
KW - Endocytosis
KW - CTLA-4 Antigen/immunology
KW - DNA/immunology
KW - B7-H1 Antigen/immunology
KW - Neoplasms/immunology
KW - Cell Differentiation
KW - Cytokines/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85038640821&partnerID=8YFLogxK
U2 - 10.1097/CJI.0000000000000195
DO - 10.1097/CJI.0000000000000195
M3 - Journal article
C2 - 29189388
SN - 1524-9557
VL - 41
SP - 9
EP - 18
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 1
ER -