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STING signaling is a potential immunotherapeutic target in colorectal cancer.

ABSTRACT: Background: Stimulator of Interferon Genes (STING) is an innate immune sensor for cytosolic DNA. STING signaling activation is indispensable for type I interferon response and the anti-cancer immune response by CD8+ T cells. The aim of this study was to characterize intratumoral STING expression pattern and its clinical implication in colorectal cancer (CRC). Methods: We analyzed STING and CD8 expression in 225 CRC patients who underwent surgical resection. Clinicopathological variables and survival outcomes were analyzed according to STING expression levels. Mice with syngeneic MC38 tumors were also treated with a STING agonist, and tumor microenvironments were analyzed using immunofluorescent staining and flow cytometry. Results: Distinct STING expression was observed in the CRC tumor specimens. Patients with higher STING expression had early stage cancer with increased intratumoral CD8+ T cell infiltration and less frequent lymphovascular invasion. Compared to CRC patients with lower STING expression, those with higher STING expression had longer overall and recurrence-free survival. Multivariate Cox regression model also revealed higher STING expression to be an independent prognostic factor for better overall survival. When MC38 colon tumors were treated with intratumoral injection of STING agonist, tumor growth was remarkably suppressed with increased intratumoral CD8+ T cell infiltration. Moreover, T-cell activation markers, ICOS and IFN-?, were also upregulated in CD8+ T cells, indicating enhanced effector T cell function after STING treatment. Conclusion: We confirmed the distinct STING expression in CRC and demonstrated its independent prognostic value in survival outcomes. STING could be a potential therapeutic target that enhances anti-cancer immune response in CRC.

SUBMITTER: Chon HJ

PROVIDER: S-EPMC6775531 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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STING signaling is a potential immunotherapeutic target in colorectal cancer.

Chon Hong Jae HJ Kim Hyojoong H Noh Jung Hyun JH Yang Hannah H Lee Won Suk WS Kong So Jung SJ Lee Seung Jun SJ Lee Yu Seong YS Kim Woo Ram WR Kim Joo Hang JH Kim Gwangil G Kim Chan C

Journal of Cancer 20190827 20

Background: Stimulator of Interferon Genes (STING) is an innate immune sensor for cytosolic DNA. STING signaling activation is indispensable for type I interferon response and the anti-cancer immune response by CD8+ T cells. The aim of this study was to characterize intratumoral STING expression pattern and its clinical implication in colorectal cancer (CRC). Methods: We analyzed STING and CD8 expression in 225 CRC patients who underwent surgical resection. Clinicopathol ...[more]

PMID: 31598165

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Project description:A major complication of colorectal cancer (CRC), one of the most common and fatal types of cancers, is secondary liver metastasis. For patients with this fate, there are very few biomarkers available in clinical application, and the disease remains incurable. Recently, increasing studies demonstrated that tumorigenesis and development are closely related to immune escape, indicating that the roles of immune-related indicators might have been neglected in the past in colorectal cancer liver metastases (CRLM). Here, we unveil that elevated miR-425 and miR-576 promote CRLM through inhibiting PTEN-mediated cellular immune function. Specifically, miR-425 and miR-576 were identified for their significant upregulation in CRLM compared with the primary CRC tissues based on GSE81581 (n = 8) and GSE44121 (n = 18) datasets. Besides, we determined that the two microRNAs (miRNAs) coparticipated in restraining P53 and transforming growth factor beta (TGF-β) signaling pathways associated with tumor metastasis, and both shortened the overall survival of the patients with metastatic susceptibility. Notably, in situ hybridization on relatively large samples of paired CRC tissues (n = 157) not only substantiated that the expression of miR-425 and miR-576 was dramatically upregulated in CRLM but also revealed that they were closely related to tumor deterioration, especially liver metastases. Moreover, we further confirmed that the combination of miR-425 and miR-576 was an effective predictive model for liver metastases and poor clinical outcomes. Mechanically, downregulated PTEN (GSE81558, n = 6) was verified to be a shared target of miR-425 and miR-576 acting as metastasis-related oncogenes, on account of the presence of binding sites (+2928-+2934 and +4371-+4378, respectively) and the collaborative suppression of P53/TGF-β signaling in CRLM, which was further confirmed in CRC cells (HCT116 and SW480) based on systematic molecular biology experiments. Importantly, the target PTEN was strongly associated with microsatellite instability, tumor microenvironment, and immune cell infiltration. Thus, we speculate that miR-425 and miR-576 are novel biomarkers for CRLM prevention and immunotherapy and upstream inhibitors of the PTEN-P53/TGF-β function axis.

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STING signaling is a potential immunotherapeutic target in colorectal cancer.

Publications

STING signaling is a potential immunotherapeutic target in colorectal cancer.

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