cGAS in action: Expanding roles in immunity and inflammation

Science, Journal Year: 2019, Volume and Issue: 363(6431)

Published: March 8, 2019

DNA is highly immunogenic. It represents a key pathogen-associated molecular pattern (PAMP) during infection. Host can, however, also act as danger-associated (DAMP) and elicit strong inflammatory responses. The cGAS-STING pathway has emerged major that detects intracellular DNA. Here, we highlight recent advances on how cGAS STING mediate responses these are regulated, allowing cells to readily respond infections noxious agents while avoiding the inappropriate sensing of self-DNA. A particular focus placed role in context sterile conditions. Manipulating or may open door for new therapeutic strategies treatment acute chronic inflammation relevant many human diseases.

Language: Английский

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DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: April 30, 2020

Abstract Radiotherapy is one of the most common countermeasures for treating a wide range tumors. However, radioresistance cancer cells still major limitation radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers improving outcomes radiotherapy. DNA double-strand breaks lethal lesions induced by ionizing radiation can trigger series cellular damage responses (DDRs), including those helping recover from injuries, such as activation sensing early transduction pathways, cell cycle arrest, repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy overcoming radioresistance, some important advances breakthroughs have already been achieved in recent years. On basis comprehensively reviewing signal we provide update on novel promising druggable emerging that be exploited radiosensitization. We further discuss identified preclinical studies, current clinical trials, application chemical inhibitors targeting key proteins, DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia–telangiectasia mutated Rad3-related), MRN (MRE11-RAD50-NBS1) complex, PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, HIF-1 (hypoxia-inducible factor-1). Challenges radiation-induced targeted therapy also discussed based achievements biological field

Language: Английский

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Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11

Cancer Discovery, Journal Year: 2019, Volume and Issue: 9(12), P. 1673 - 1685

Published: Sept. 25, 2019

Abstract A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment ferroptosis antagonists limit efficacy tumor models. Immunotherapy sensitizes tumors by promoting Mechanistically, IFNγ derived from immunotherapy-activated CD8+ T cells radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate–cystine antiporter xc−, resulting reduced cystine uptake, enhanced lipid oxidation ferroptosis, improved control. Thus, an unappreciated mechanism focus for development effective combinatorial cancer therapy. Significance: This article describes as previously action Further, it shows novel point synergy between Finally, nominates critical regulator mechanistic determinant immunotherapy. highlighted In Issue feature, p. 1631

Language: Английский

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Radiotherapy induces responses of lung cancer to CTLA-4 blockade

Nature Medicine, Journal Year: 2018, Volume and Issue: 24(12), P. 1845 - 1851

Published: Oct. 24, 2018

Language: Английский

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Harnessing innate immunity in cancer therapy

Nature, Journal Year: 2019, Volume and Issue: 574(7776), P. 45 - 56

Published: Oct. 2, 2019

Language: Английский

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Phagocytosis checkpoints as new targets for cancer immunotherapy

Nature reviews. Cancer, Journal Year: 2019, Volume and Issue: 19(10), P. 568 - 586

Published: Aug. 28, 2019

Language: Английский

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Inflammatory microenvironment remodelling by tumour cells after radiotherapy

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(4), P. 203 - 217

Published: March 11, 2020

Language: Английский

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The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment

Cell, Journal Year: 2018, Volume and Issue: 174(6), P. 1347 - 1360

Published: Sept. 1, 2018

Language: Английский

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Context is everything: aneuploidy in cancer

Nature Reviews Genetics, Journal Year: 2019, Volume and Issue: 21(1), P. 44 - 62

Published: Sept. 23, 2019

Language: Английский

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PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer

Cancer Discovery, Journal Year: 2019, Volume and Issue: 9(6), P. 722 - 737

Published: April 23, 2019

Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects inhibition have been incompletely studied. Here, we sought to dissect mechanisms underlying inhibitor-induced changes in tumor microenvironment BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that inhibitor olaparib induces CD8+ T-cell infiltration and activation vivo, depletion severely compromises antitumor efficacy. Olaparib-induced recruitment is mediated through cGAS/STING pathway cells paracrine dendritic more pronounced HR-deficient compared HR-proficient TNBC vivo models. CRISPR-mediated knockout STING prevents proinflammatory signaling sufficient abolish olaparib-induced vivo. These findings elucidate an additional mechanism action provide a rationale for combining treatment TNBC. SIGNIFICANCE: This work demonstrates cross-talk between related STING/TBK1/IRF3 governs The data insight into BRCA-associated cancer.This article highlighted In Issue feature, p. 681.

Language: Английский

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