DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

Vanpouille-Box, Claire; Alard, Amandine; Aryankalayil, Molykutty J.; Sarfraz, Yasmeen; Diamond, Julie M.; Schneider, Robert J.; Inghirami, Giorgio; Coleman, C. Norman; Formenti, Silvia C.; Demaria, Sandra

doi:10.1038/ncomms15618

Cited by 1,261 publications

(1,264 citation statements)

References 39 publications

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“…Seminal studies using breast cancer models showed that the DNA exonuclease 3 repair exonuclease 1 (TREX1) inhibits immune activation 45,46 . TREX1 is induced by radiation doses above 12–18 Gy in different colorectal carcinoma and breast cancer cell lines, and it attenuates immunogenicity by degrading double-strand DNA that accumulates in the cytosol upon radiation 47 . Further investigations of dosage and combinations of radiotherapy with immunotherapy are needed to determine the optimal thresholds or range 48 .…”

Section: Boosting the Abscopal Effectmentioning

confidence: 99%

Using immunotherapy to boost the abscopal effect

et al. 2018

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More than 60 years ago, the effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the abscopal effect (from ‘ab scopus’, that is, away from the target). The abscopal effect has been connected to mechanisms involving the immune system. However, the effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the abscopal effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.

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Section: Boosting the Abscopal Effectmentioning

confidence: 99%

Using immunotherapy to boost the abscopal effect

et al. 2018

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“…Notably, in ALT cancer cells cytosolic DNA sensing is defective, suggesting that loss of cell-intrinsic self-DNA sensing is requirement for transformation and maintenance of ALT cells. Mammary tumor cells subjected to increasing doses of radiation therapy also accumulate DNA in the cytoplasm, which correlates with cGAS-mediated expression of IFN-I and IFN-I stimulated genes [58]. TREX1 is an important regulator of the intrinsic process, as it is up-regulated at high doses of radiation and drives attenuation of the immunogenic signal.…”

Section: Cancer Cancer Therapy and Genotoxic Stressmentioning

confidence: 99%

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

Dhanwani

Takahashi

Sharma

2018

Current Opinion in Immunology

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In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2′–5′-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS–STING–IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults.

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“…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

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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.

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DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

Cited by 1,261 publications

References 39 publications

Using immunotherapy to boost the abscopal effect

Using immunotherapy to boost the abscopal effect

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

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

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