دورية أكاديمية
STING activation normalizes the intraperitoneal vascular-immune microenvironment and suppresses peritoneal carcinomatosis of colon cancer
| العنوان: | STING activation normalizes the intraperitoneal vascular-immune microenvironment and suppresses peritoneal carcinomatosis of colon cancer |
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| المؤلفون: | Jeong Hun Kim, Yu Seong Lee, Won Suk Lee, Seung Joon Lee, Hannah Yang, So Jung Kong, Beodeul Kang, Woo Ram Kim, Hong Jae Chon, Chan Kim, Hye Jin Lee, Jaekyung Cheon |
| المصدر: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 6 (2021) |
| بيانات النشر: | BMJ Publishing Group, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Background Peritoneal carcinomatosis is a fatal clinical presentation of colon cancer, characterized by unresponsiveness to conventional anticancer therapies, including immune checkpoint inhibitors. Here, we elucidated the immune-evasion mechanisms during the peritoneal carcinomatosis of colon cancer and developed a novel immunotherapy by activating the stimulator of interferon genes (STING) pathway.Methods We generated a syngeneic peritoneal carcinomatosis model of colon cancer. Mice were intraperitoneally treated with either STING agonist (MIW815, also known as ADU-S100) or PD-1 blockade or both. The tumor microenvironment was comprehensively analyzed using multiplexed immunofluorescence imaging, flow cytometry, and NanoString immune profiling.Results Intraperitoneal colon cancer cells induce a massive influx of immunosuppressive M2-like macrophages, upregulate immune checkpoints, and impair effector T cell functions during peritoneal dissemination; these collectively create a highly angiogenic and immunosuppressive milieu that is resistant to anti-PD-1 monotherapy. Intraperitoneal administration of a STING agonist suppressed aberrant angiogenesis, increased pericyte coverage, and normalized tumor vessels, thereby facilitating the infiltration of activated CD8+ T cells into peritoneal tumor nodules. Moreover, STING activation reprogramed tumor-associated macrophages toward the M1 phenotype. STING activation converted immunologically cold peritoneal tumors into T-cell-inflamed tumors in a type-I interferon-dependent manner. Lastly, the STING agonist synergistically cooperated with PD-1 and/or COX2 blockade to further suppress the peritoneal dissemination of colon cancer, resulting in complete eradication of tumor and ascites, and inducing durable antitumor immunity.Conclusions STING activation can normalize the peritoneal vascular and immune microenvironment, providing a rationale for a novel combination therapeutic strategy for peritoneal carcinomatosis in colon cancer. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2020-0021 2051-1426 15431193 |
| Relation: | https://jitc.bmj.com/content/9/6/e002195.full; https://doaj.org/toc/2051-1426 |
| DOI: | 10.1136/jitc-2020-002195 |
| URL الوصول: | https://doaj.org/article/ea641625dd15431193bb95677a67488f |
| رقم الأكسشن: | edsdoj.641625dd15431193bb95677a67488f |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 20200021 20511426 15431193 |
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| DOI: | 10.1136/jitc-2020-002195 |