Combination of STING and TLR 7/8 Agonists as Vaccine Adjuvants for Cancer Immunotherapy

• Published in: Cancers Vol. 14; no. 24; p. 6091
• Main Authors: Bhatnagar, Shubhmita, Revuri, Vishnu, Shah, Manan, Larson, Peter, Shao, Zekun, Yu, Daohai, Prabha, Swayam, Griffith, Thomas S, Ferguson, David, Panyam, Jayanth
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2022; MDPI
• Subjects: Adjuvants; Agonists; Agonists (Biochemistry); Antigen presentation; Antigen-presenting cells; Antigens; Antitumor activity; Blood; Bone marrow; Cancer; cancer immunotherapy; cancer vaccine; Cancer vaccines; Care and treatment; CD8 antigen; Cell activation; Cytokines; Cytotoxicity; Dendritic cells; DMXAA; Dosage and administration; Flow cytometry; Growth inhibition; Health aspects; Immunological adjuvants; Immunostimulation; Immunotherapy; Inflammation; Interleukin 10; Kinases; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Macrophages; Melanoma; Methods; Natural killer cells; Pathogens; Proteins; Spleen; STING; TLR7; Toll-like receptors; Tumor necrosis factor-TNF; Tumors; Vaccines; Variance analysis; γ-Interferon; United States; United States > US; STING; toll-like receptors; cancer vaccine; DMXAA; cancer immunotherapy
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14246091

Immunostimulatory adjuvants that potently activate antigen-presenting cells and (in turn) prime cytotoxic T cells are a key component of anticancer vaccines. In this study, we investigated a multi-adjuvant approach combining a TLR 7/8 agonist (522) and a STING agonist (DMXAA) to promote enhanced antigen cross-presentation, stimulate specific antitumor T-cell responses, and provide improved anticancer efficacy. In vitro experiments using bone marrow-derived dendritic cells (BMDCs) confirmed enhanced activation with the 522-DMXAA combination based on both co-stimulatory molecule expression and pro-inflammatory cytokine secretion. The immunization of mice with vaccines comprising both 522 and DMXAA resulted in greater antitumor efficacy in B16F10 melanoma and MB49 bladder tumor models relative to mono-agonist vaccines. Flow cytometry-based analysis of immune cells from immunized mice revealed the significant activation of antigen-presenting cells, increased numbers of activated and Ag-specific CD8+ T cells in the spleen and lymph nodes, modest NK cell activation, and an overall reduction in CD206 macrophages. These results were supported by an increase in the levels of IFN-γ and a reduction in IL-10 levels in the sera. Taken together, these findings demonstrate the potential of the TLR7/8 and STING agonist combination as vaccine adjuvants to activate both innate and adaptive immune responses.