Journal
THERANOSTICS
Volume 10, Issue 2, Pages 498-515Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.37745
Keywords
Gastric carcinoma; STING; apoptosis; IL-24; IL-6R
Categories
Funding
- National Key RAMP
- D Program of China [2018A030313808, 2018YFC1313300]
- National Postdoctoral Program for innovative Talents [BX201600197]
- National Natural Science Foundation of China [2018M643340]
- Precision Oncology Research Program of Guangdong Province [GDACA001]
- China Postdoctoral Science Foundation [2017M622886]
- Science and Technology Program of Guangdong [2019B020227002]
- Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences [2019RU032]
Ask authors/readers for more resources
Rationale: STING is a critical player in the innate and adaptive immune system, sensing cytosolic DNA to activate the expression of interferon genes and regulate T lymphocytes, which drives immunogenic responses to cancer cells. Tumor-associated macrophages (TAMs), abundantly present in the tumor microenvironment, play a key role in cancer development. Gastric cancer is one of the most common and leading causes in cancer-related death worldwide. However, studies on the function and regulation of STING in TAMs and their roles in gastric cancer progression are still limited. Methods: We analyzed STING and CD68 expression of 200 pairs of gastric cancer and adjacent normal tissues by immunohistochemistry to identify the prognostic values of STING, as well as the correlations between STING and CD68 in gastric cancer. The characteristics of STING-altered macrophages, as well as their effects on cancer cell apoptosis and T cell differentiation were examined by flow cytometry. Cytokines secreted by STING-altered macrophages were identified by the Human Inflammation Array3 kit. Concentrations of soluble IL24 and IFN-beta were measured by ELISA. In vivo models, including spontaneous gastric cancer in p53(+/-) mice and cell line-based xenografts, were established, and clinical benefits of STING-altered macrophages were examined. Results: Our study identifies STING as a prognostic factor for gastric cancer, and for the first time demonstrated that knocking-down STING and STING activation by 2'3'-c-GAMP both promote TAMs polarizing into pro-inflammatory subtype and induce apoptosis of gastric cancer cells, mechanistically through IL6R-JAK-IL24 pathway. Conclusions: This study evaluated effects of targeting STING in TAMs in anti-gastric-cancer therapies. Moreover, we unveil a novel function of STING to activate the IL6R-JAK-IL24 pathway in macrophages.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available