Yonsei Med J.  2022 Jan;63(1):42-55. 10.3349/ymj.2022.63.1.42.

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

• Synn CB
• Kim DK
• Kim JH
• Byeon Y
• Kim YS
• Yun MR
• Lee JM
• Lee W
• Lee EJ
• Lee S
• Lee YW
• Lee DJ
• Kim HW
• Kim CG
• Hong MH
• Park JD
• Lim SM
• Pyo KH

• KMID: 2523332
• DOI: http://doi.org/10.3349/ymj.2022.63.1.42

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.

Keyword

STING agonist; skin metastasis; lung cancer; T cell-mediated immune response; macrophages