STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors

Deng, Lu; Liang, Hua; Xu, Meng; Yang, Xuanming; Burnette, Byron; Arina, Ainhoa; Li, Xiao Dong; Mauceri, Helena J.; Beckett, Michael A.; Darga, Thomas E.; Huang, Xiaona; Gajewski, Thomas F.; Chen, Zhijian J.; Fu, Yang Xin; Weichselbaum, Ralph R.

doi:10.1016/j.immuni.2014.10.019

Cited by 1,639 publications

(1,560 citation statements)

References 43 publications

Supporting

Mentioning

1,516

Contrasting

Unclassified

Order By: Relevance

“…6,15–17 Investigations in different mouse tumor models revealed that radiotherapy-induced anti-tumor immune reactions, which are essentially dependent on type-I interferons (produced by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) axis), APCs, and cytotoxic CD8 + T cells, are exclusively stimulated by high single doses (10–20 Gy). 18–23 On the contrary, a recent study suggests that 3 × 8 Gy may be optimal. 24 Clinically, abscopal tumor lesion regression remains rare, most likely because comparable super-hypofractionated protocols (fractions of >5 Gy) are rarely used in the radiotherapeutic routine.…”

Section: Introductionmentioning

confidence: 99%

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

et al. 2018

View full text Add to dashboard Cite

The major goal of radiotherapy is the induction of tumor cell death. Additionally, radiotherapy can function as in situ cancer vaccination by exposing tumor antigens and providing adjuvants for anti-tumor immune priming. In this regard, the mode of tumor cell death and the repertoire of released damage-associated molecular patterns (DAMPs) are crucial. However, optimal dosing and fractionation of radiotherapy remain controversial. Here, we examined the initial steps of anti-tumor immune priming by different radiation regimens (20 Gy, 4 × 2 Gy, 2 Gy, 0 Gy) with cell lines of triple-negative breast cancer in vitro and in vivo. Previously, we have shown that especially high single doses (20 Gy) induce a delayed type of primary necrosis with characteristics of mitotic catastrophe and plasma membrane disintegration. Now, we provide evidence that protein DAMPs released by these dying cells stimulate sequential recruitment of neutrophils and monocytes in vivo. Key players in this regard appear to be endothelial cells revealing a distinct state of activation upon exposure to supernatants of irradiated tumor cells as characterized by high surface expression of adhesion molecules and production of a discrete cytokine/chemokine pattern. Furthermore, irradiated tumor cell-derived protein DAMPs enforced differentiation and maturation of dendritic cells as hallmarked by upregulation of co-stimulatory molecules and improved T cell-priming. Consistently, a recurring pattern was observed: The strongest effects were detected with 20 Gy-irradiated cells. Obviously, the initial steps of radiotherapy-induced anti-tumor immune priming are preferentially triggered by high single doses – at least in models of triple-negative breast cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

et al. 2018

View full text Add to dashboard Cite

show abstract

“…STAT1 phosphorylation can be elicited following activation of the DNA dependent pattern recognition receptor (PRR) cGAS and its downstream mediators STING and IRF3, which serve to transcriptionally activate type I interferon 8–16 . CRISPR-Cas9 knockout of either cytosolic cGAS or STING reduced activation of downstream IRF3 target genes ISG54, ISG56 and the NF-κB target CCL5 post-IR (Fig 3a and Extended data 3a) 17, 18 .…”

mentioning

confidence: 99%

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Harding

Benci

Irianto

et al. 2017

Nature

1,175

780

View full text Add to dashboard Cite

Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumor microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumor responses to radiotherapy1. An enigmatic feature of this phenomenon is its delayed onset (days), in contrast to the acute DNA damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate limiting steps that are essential for DNA-damage induced inflammation. Here, we show that cell cycle progression through mitosis following DNA double-strand breaks (DSBs) leads to the formation of micronuclei, which precede activation of inflammatory signaling and are a repository for the pattern recognition receptor cGAS. Inhibiting progression through mitosis or loss of pattern recognition by cGAS-STING impaired interferon signaling. Moreover, STING loss prevented the regression of abscopal tumors in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.

show abstract

“…By contrast, inhibition of HMGB1 or knockout of downstream TLR4 signaling components has no effect on subcutaneous colon cancer cells following radiotherapy [99]. In this model, radiotherapy response is dependent on type I IFN signaling in dendritic cells and the adaptor protein STING [98,99]. Whether the discrepancy between the roles of myeloid cells in these studies is caused by the differences in tumor model, or by the differences in radiotherapy dose and schedule remains to be investigated.…”

Section: Innate Immune Cellsmentioning

confidence: 86%

“…For example, HMGB1-sensing TLR4 + dendritic cells are required for radiotherapy efficacy in subcutaneous thymomas [58]. By contrast, inhibition of HMGB1 or knockout of downstream TLR4 signaling components has no effect on subcutaneous colon cancer cells following radiotherapy [99]. In this model, radiotherapy response is dependent on type I IFN signaling in dendritic cells and the adaptor protein STING [98,99].…”

Section: Innate Immune Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

View full text Add to dashboard Cite

SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

show abstract

STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors

Cited by 1,639 publications

References 43 publications

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Contact Info

Product

Resources

About