Primary Tumor Suppression and Systemic Immune Activation of Macrophages through the Sting Pathway in Metastatic Skin Tumor

Abstract

Purpose Agonists of the stimulator of interferon genes (STING) play a key role in activating the STING pathway by promoting the production of cytokines. In this study, we investigated the antitumor effects and activation of the systemic immune response of treatment with DMXAA (5,6-dimethylxanthenone-4-acetic acid), a STING agonist, in EML4-ALK lung cancer and CT26 colon cancer. Materials and Methods The abscopal effects of DMXAA in the treatment of metastatic skin nodules were assessed. EML4-ALK lung cancer and CT26 colon cancer models were used to evaluate these effects after DMXAA treatment. To evaluate the expression of macrophages and T cells, we sacrificed the tumor-bearing mice after DMXAA treatment and obtained the formalin-fixed paraffin-embedded (FFPE) tissue and tumor cells. Immunohistochemistry and flow cytometry were performed to analyze the expression of each FFPE and tumor cell. Results We observed that highly infiltrating immune cells downstream of the STING pathway had increased levels of chemokines after DMXAA treatment. In addition, the levels of CD80 and CD86 in antigen-presenting cells were significantly increased after STING activation. Furthermore, innate immune activation altered the systemic T cell-mediated immune responses, induced proliferation of macrophages, inhibited tumor growth, and increased numbers of cytotoxic memory T cells. Tumor-specific lymphocytes also increased in number after treatment with DMXAA. Conclusion The abscopal effect of DMXAA treatment on the skin strongly reduced the spread of EML4-ALK lung cancer and CT26 colon cancer through the STING pathway and induced the presentation of antigens.

Gene signature from cutaneous autoimmune diseases provides potential immunotherapy-relevant biomarkers in melanoma

“…T cells from skin-derived inflammatory diseases exhibit differential gene expression patterns, including genes known to be involved in immune activation in cancer 44 . Specifically, in tumors, IFN-related genes are recognized to activate T cells and play a crucial role in tumor infiltration.…”

Role of STING in the treatment of non-small cell lung cancer

“…5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a flavonoid with putative anti-tumor activity, was originally developed as an anti-angiogenic agent and was later found to interact directly with STING [ 59 ]. Although phase III clinical trials did not demonstrate any improvement in the prognosis of NSCLC patients treated with DMXAA in combination with standard chemotherapy [ 60 ], researchers have revealed that the expression levels of TNF-α, IFN-β, and STING were significantly up-regulated in EML4-ALK NSCLC tumors after DMXAA treatment, which resulted in the inhibition of tumor growth and the induction of strong anti-tumor immunity in EML4-ALK NSCLC mouse models [ 61 ]. EML4-ALK is a unique molecular subgroup of lung cancer that is resistant to checkpoint inhibitors [ 62 ].…”

The diverse influences of relaxin-like peptide family on tumor progression: Potential opportunities and emerging challenges

“…Conversely, upon stimulation with lipopolysaccharide and interferon (IFN)-γ, RLN does not affect Arg-1 expression but promotes the upregulation of iNOS expression. This suggests a mechanism distinct from the classical mechanism of macrophage polarization [ 99 , 105 ]. RLN-RXFP1 signaling stimulates the secretion of IL-1β and TNF-α in PBMCs [ 106 ].…”