STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation

Takashima, Ken; Takeda, Yohei; Oshiumi, Hiroyuki; Shime, Hiroaki; Okabe, Masaru; Ikawa, Masahito; Matsumoto, Misako; Seya, Tsukasa

doi:10.1016/j.bbrc.2016.09.021

Cited by 76 publications

(62 citation statements)

References 23 publications

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“…Further, differential expression of STING in cancer cells and stromal support cells, as well as differential levels of immune suppression suggest that STING agonist effects are likely variable and tumor-dependent. For instance, deletion of STING in B16D8 melanoma cells has been demonstrated to have minimal impact on cell survival [70], and administration of STING agonists did not affect cell growth of B16F10, SCCFVII, or CT26 cells [71,72]. In contrast, breast cancer cell lines 4 T1, MCF-7, and T47D appear sensitive to changes in STING expression or administration of STING agonists [73,74].…”

Section: Discussionmentioning

confidence: 99%

STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models

Jing¹,

McAllister

Vonderhaar

et al. 2019

j. immunotherapy cancer

138

102

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Pancreatic cancer is characterized by an immune suppressive stromal reaction that creates a barrier to therapy. A murine transgenic pancreatic cancer cell line that recapitulates human disease was used to test whether a STimulator of Interferon Genes (STING) agonist could reignite immunologically inert pancreatic tumors. STING agonist treatment potently changed the tumor architecture, altered the immune profile, and increased the survival of tumor-bearing mice. Notably, STING agonist increased numbers and activity of cytotoxic T cells within tumors and decreased levels of suppressive regulatory T cells. Further, STING agonist treatment upregulated costimulatory molecule expression on cross-presenting dendritic cells and reprogrammed immune-suppressive macrophages into immune-activating subtypes. STING agonist promoted the coordinated and differential cytokine production by dendritic cells, macrophages, and pancreatic cancer cells. Cumulatively, these data demonstrate that pancreatic cancer progression is potently inhibited by STING agonist, which reignited immunologically cold pancreatic tumors to promote trafficking and activation of tumor-killing T cells.

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Section: Discussionmentioning

confidence: 99%

STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models

Jing¹,

McAllister

Vonderhaar

et al. 2019

j. immunotherapy cancer

138

102

View full text Add to dashboard Cite

show abstract

“…Intratumoral administration of STING agonists also potently primed tumor antigen–specific CD8 T cell responses and enhanced the anti-tumor effect of PD-L1 and OX-40 targeted therapy [31]. Additionally, STING in tumor and host immune cells cooperatively work for NK cell-mediated tumor growth retardation [32]. Clinical treatment efficacy of cetuximab is limited to 15%-20% of patients and the underlying mechanism of action suggest a link to NK cell mediated cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

Concha-Benavente

Shayan

et al. 2018

Oral Oncology

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Objectives The intracellular DNA sensor stimulator of interferon genes (STING) has recently been shown to play a vital role in anti-viral and anti-tumor immune responses stimulating cytokine production. While human papillomavirus (HPV) is a causative agent for a subset of head and neck squamous cell carcinoma (HNSCC) with unique etiology and clinical outcome, how the STING pathway is regulated in a virus-induced tumor microenvironment is not well understood. Since STING inactivation likely reflects immunoescape via innate immunity, we hypothesized that its restoration would improve efficacy of the immune modulatory monoclonal antibody (mAb), cetuximab. Materials and methods We correlated STING protein expression with clinical parameters by immunohistochemistry (n = 106) and its mRNA expression from The Cancer Genome Atlas (TCGA) in HNSCC tissue specimens. STING protein expression was tested for association with cancer-specific survival (CSS). We further examined the impact of STING activation on cetuximab-mediated immunity using an in vitro NK:DC:tumor cells co-culture system. Results In this study, we found that expression of STING both at the protein and mRNA level was higher in HPV positive (HPV+) specimens but unrelated to TNM stage or cancer-specific survival. Our in vitro studies verified that STING activation enhanced cetuximab mediated NK cell activation and DC maturation. Conclusion Our findings suggest a novel role of STING in HPV-related carcinogenesis, in which activation of the STING signaling pathway may facilitate anti-tumor response in HNSCC patients, particularly in combination with therapeutic monoclonal antibodies (mAbs) such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor.

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“…Ticam‐1 −/− and Mavs −/− mice were generated in our laboratory . STING‐deficient ( Tmem173 −/− ) mice were developed in our laboratory by CRISPR/Cas9 method as previously reported . Mice 6‐14 weeks old were used and maintained under specific pathogen‐free conditions.…”

Section: Methodsmentioning

confidence: 99%

Toll‐like receptor 3 signal augments radiation‐induced tumor growth retardation in a murine model

et al. 2018

Self Cite

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Radiotherapy induces anti‐tumor immunity by induction of tumor antigens and damage‐associated molecular patterns (DAMP). DNA, a representative DAMP in radiotherapy, activates the stimulator of interferon genes (STING) pathway which enhances the immune response. However, the immune response does not always parallel the inflammation associated with radiotherapy. This lack of correspondence may, in part, explain the radiation‐resistance of tumors. Additive immunotherapy is expected to revive tumor‐specific CTL facilitating radiation‐resistant tumor shrinkage. Herein pre‐administration of the double‐stranded RNA, polyinosinic‐polycytidylic acid (polyI:C), in conjunction with radiotherapy, was shown to foster tumor suppression in mice bearing radioresistant, ovalbumin‐expressing Lewis lung carcinoma (LLC). Extrinsic injection of tumor antigen was not required for tumor suppression. No STING‐ and CTL‐response was induced by radiation in the implant tumor. PolyI:C was more effective for induction of tumor growth retardation at 1 day before radiation than at post‐treatment. PolyI:C targeted Toll‐like receptor 3 with minimal effect on the mitochondrial antiviral‐signaling protein pathway. Likewise, the STING pathway barely contributed to LLC tumor suppression. PolyI:C primed antigen‐presenting dendritic cells in draining lymph nodes to induce proliferation of antigen‐specific CTL. By combination therapy, CTL efficiently infiltrated into tumors with upregulation of relevant chemokine transcripts. Batf3‐positive DC and CD8+ T cells were essential for therapeutic efficacy. Furthermore, polyI:C was shown to stimulate tumor‐associated macrophages and release tumor necrosis factor alpha, which acted on tumor cells and increased sensitivity to radiation. Hence, polyI:C treatment prior to radiotherapy potentially induces tumor suppression by boosting CTL‐dependent and macrophage‐mediated anti‐tumor responses. Eventually, polyI:C and radiotherapy in combination would be a promising therapeutic strategy for radiation‐resistant tumors.

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STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation

Cited by 76 publications

References 23 publications

STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models

STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models

STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

Toll‐like receptor 3 signal augments radiation‐induced tumor growth retardation in a murine model

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