The <scp>DNA</scp> damage response induces antigen presenting cell‐like functions in fibroblasts

Tang, Melissa Li Fang; Khan, Muznah; Croxford, J. Ludovic; Tan, Kui‐Thong; Angeli, Véronique; Gasser, Stephan

doi:10.1002/eji.201343781

Cited by 23 publications

(14 citation statements)

References 42 publications

(56 reference statements)

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“…36 Data from several other reports have revealed that the DNA damage responses mediated by ATR, ATM and CHEK1 may alert the immune system to the presence of potentially dangerous cells by upregulating the expression of ligands that can induce the activation of innate and adaptive immune cells. 37,38 Our current study provides novel evidence for a critical role of the ATR-CHEK1 axis activation in mediating the proinflammatory response in bronchial epithelial cells under PM2.5 exposure (Figs. 6 to 8), further confirming the functional link between checkpoint pathways and immune responses under particle-induced stress.…”

Section: Discussionmentioning

confidence: 65%

“…26,27 In the light of recent studies, functional links between the immune response and the ATR-CHEK1-mediated processes that regulate genomic integrity have also been revealed. [35][36][37][38] For example, the ATR-CHEK1 pathway was found to be activated in the Simian virus 40 large T antigen-induced DNA damage response in human fibroblasts, resulting in the induction of IRF1 (interferon regulatory factor 1) and the transactivation of IFNB1 (interferon b 1) to mediate the antiviral response. 35 Intriguingly, in germinal center B cells, downregulation of the ATR-CHEK1 checkpoint axis is required for efficient somatic hypermutation and IgG diversification.…”

Section: Discussionmentioning

confidence: 99%

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TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5)

Wang

et al. 2016

Autophagy

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Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with a number of pathological respiratory diseases, such as bronchitis, asthma, and chronic obstructive pulmonary disease, which share the common feature of airway inflammation induced by particle exposure. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is crucial for the study of PM2.5 toxicity. In the current study, we found that exposing human bronchial epithelial cells (immortalized Beas-2B cells and primary cells) to PM2.5 collected in the winter in Wuhan, a city in southern China, induced a significant upregulation of VEGFA (vascular endothelial growth factor A) production, a signaling event that typically functions to control chronic airway inflammation and vascular remodeling. Further investigations showed that macroautophagy/autophagy was induced upon PM2.5 exposure and then mediated VEGFA upregulation by activating the SRC (SRC proto-oncogene, non-receptor tyrosine kinase)-STAT3 (signal transducer and activator of transcription 3) pathway in bronchial epithelial cells. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 (tumor protein p53) activation and the expression of its downstream target DRAM1 (DNA damage regulated autophagy modulator 1) for the induction of autophagy. These results thus extend the role of TP53-DRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2.5 exposure strongly induced the activation of the ATR (ATR serine/threonine kinase)-CHEK1/CHK1 (checkpoint kinase 1) axis, which subsequently triggered TP53-dependent autophagy and VEGFA production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5)

Wang

et al. 2016

Autophagy

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“…In addition to altering the extrinsic immunogenicity of tumors at the level of the microenvironment, DNA damage can also alter the intrinsic immunogenicity of tumor cells through modulation of surface phenotype. For example, studies of aphidicolin and cytarabine have shown the ability of DNA-damaging agents to drive upregulation of natural-killer group 2, member D ligands, inducible T-cell costimulator (ICOS) ligand and MHC class I, in an ATM-or ATR-dependent manner (76,77). These studies, though not directly related to PARP inhibition, suggest that increased DNA damage can make cells more visible to, and sensitive to killing by, T cells and natural killer (NK) cells, through modulation of surface phenotype.…”

Section: Fundamental Links Between Dna Damage Inflammation Cancer Pmentioning

confidence: 99%

Development of PARP and Immune-Checkpoint Inhibitor Combinations

2018

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PARP inhibitors drive increased DNA damage, particularly in tumors with existing defects in DNA repair. This damage not only promotes immune priming through a range of molecular mechanisms, but also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. In this context, PARP inhibition and programmed cell death 1 (PD-1)/PD-L1-targeting antibodies represent a rationale combination. In this review, we detail the basic and translational science underpinning this promising new combination, summarize available clinical data, and discuss the key questions that remain to be addressed during future development. Cancer Res; 78(24); 6717-25. Ó2018 AACR.

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“…The rationale for this combination is that inhibition of PARP will result in an increase in mutational load and modification of tumor immunogenicity, 59 , 60 resulting in an increased sensitivity to immune checkpoint inhibitors of CTLA-4, programmed cell death-1, and programmed cell death-ligand 1 (PD-L1). This is supported by preclinical data, but we are yet to see the final results of the current studies.…”

Section: Future Directions and Challenges For Rucaparib And The Classmentioning

confidence: 99%

<div>Emerging treatment options for ovarian cancer: focus on rucaparib</div>

Mariappan

Jiang

Jackson

et al. 2017

IJWH

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Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are an exciting class of anticancer drugs, which have revolutionized the management of BRCA mutant/homologous recombination-deficient recurrent high-grade serous ovarian cancer (HGSOC). With three PARPi now approved by the US Food and Drug Administration, olaparib (Lynparza™), niraparib (Zejula™), and rucaparib (Rubraca™) in 2014 (and 2017 for the tablet formulation), 2016, and 2017, respectively, these drugs have now entered routine clinical practice. The marked single-agent efficacy of PARPi either as maintenance following response to platinum-based chemotherapy or as up-front treatment in these indications is based on the well-known concept of synthetic lethality. PARPi themselves work by blocking the repair of single-strand DNA breaks by the base excision/single-strand break repair pathway and can also be directly cytotoxic by the mechanism of PARP trapping. The greatest benefit in terms of progression-free survival, in all three PARPi maintenance registration studies, was seen in women with platinum-sensitive BRCA mutation-associated HGSOC. However, it is clear that non-BRCA HGSOC can benefit from PARPi and the ongoing challenge of biomarker driven studies is how best to define these patients. PARPi are well tolerated, but more information is needed to assess the longer-term/later onset toxicities as these agents are investigated in the first-line setting. The future direction and challenges for PARPi will be to continue to expand beyond BRCA and ovarian cancer by identifying molecular or functional signatures of response; to see if the durable responses in ovarian cancer can be improved and efficacy can be achieved in other cancer sub-types by combining with novel targeted agents. This review summarizes the development of PARPi as a class in ovarian cancer with particular focus on the PARPi rucaparib.

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The DNA damage response induces antigen presenting cell‐like functions in fibroblasts

Abstract: Keywords: Adaptive immunity r Antigen-presenting cell r Chemotherapy r DNA damage r Fibroblasts Additional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 23 publications

References 42 publications

TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5)

TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5)

Development of PARP and Immune-Checkpoint Inhibitor Combinations

<div>Emerging treatment options for ovarian cancer: focus on rucaparib</div>

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