STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity

Pei, Junchen; Zhang, Hongjie; Luo, Qinhong; Zheng, Wenshan; Li, Wanxuan; Zeng, Xin; Li, Qinkai; Quan, Jing

doi:10.1016/j.canlet.2019.02.029

Cited by 51 publications

(36 citation statements)

References 57 publications

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“…Tregs, which were enriched in the tumor microenvironment in a high degree, were well known for the roles in immune suppression in tumors [66]. Following that, impeding the expression of STAT3 by some small molecules attributed to decreasing the infiltration of Tregs the tumor microenvironment [67]. FOXP3, the lineage-specification factor, is essential for maintaining the suppressor function of Tregs.…”

Section: Discussionmentioning

confidence: 99%

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

et al. 2020

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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and regulates tumorigenesis. However, the functions of STAT3 in immune and drug response in cancer remain elusive. Hence, we aim to reveal the impact of STAT3 in immune infiltration and drug response comprehensively by bioinformatics analysis. The expression of STAT3 and its relationship with tumor stage were explored by Tumor Immune Estimation Resource (TIMER), Human Protein Altas (HPA), and UALCAN databases. The correlations between STAT3 and immune infiltration, gene markers of immune cells were analyzed by TIMER. Moreover, the association between STAT3 and drug response was evaluated by the Cancer Cell Line Encyclopedia (CCLE) and Cancer Therapeutics Response Portal (CTRP). The results suggested that the mRNA transcriptional level of STAT3 was lower in tumors than normal tissues and mostly unrelated to tumor stage. Besides, the protein expression of STAT3 decreased in colorectal and renal cancer compared with normal tissues. Importantly, STAT3 was correlated with immune infiltration and particularly regulated tumor-associated macrophage (TAM), M2 macrophage, T-helper 1 (Th1), follicular helper T (Treg), and exhausted T-cells. Remarkably, STAT3 was closely correlated with the response to specified inhibitors and natural compounds in cancer. Furthermore, the association between STAT3 and drug response was highly cell line type dependent. Significantly, the study provides thorough insight that STAT3 is associated with immunosuppression, as well as drug response in clinical treatment.

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Section: Discussionmentioning

confidence: 99%

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

et al. 2020

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“…Recent evidence indicates that the combination of STING agonists with STAT3 inhibitors can enhance tumor immunogenicity and optimize the immunotherapeutic effects [ 113 , 116 ]. For example, combined STAT3 direct inhibitor HJC0152 with STING agonist c-diAM (PS)2 increased CD8 + T cells, reduced Treg cells and MDSCs in the TME, and thus effectively enhanced anti-tumor immunity in mice with breast cancer [ 113 ]. A preclinical study demonstrated the combination of STING agonist (cGAMP or RR-CDA) with the indirect STAT3 inhibitor VEGFR2 was maximally effective for immunotherapy-resistant tumors in breast and lung cancer [ 116 ].…”

Section: Integrating Stat3 In Combination Cancer Immunotherapymentioning

confidence: 99%

Targeting STAT3 in Cancer Immunotherapy

et al. 2020

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As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

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“…In terms of targeted therapies, combined treatment with cetuximab and STING agonists facilitated tumor recession in patients with HPV-positive (HPV + ) head neck squamous cell carcinoma (HNSCC), which may depend on cetuximab-mediated NK cell activation and DC maturation [156]. Additionally, Pei et al demonstrated that the STAT3 inhibitor HJC0152 (i.t., 30 μg) also enhanced the treatment effect of the STING agonist c-di-AM (PS)2 (i.t., 10 μg), leading to significant tumor rejection in a 4 T1 breast cancer model [157]. Details of all the aforementioned combination treatment regimens are available in Table 4.…”

Section: Indirect Sting Agonistsmentioning

confidence: 99%

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

et al. 2020

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Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

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STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity

Cited by 51 publications

References 57 publications

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

Targeting STAT3 in Cancer Immunotherapy

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

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