PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer

Chabanon, R; Muirhead, Gareth; Krastev, Dragomir B.; Adam, Julien; Morel, Daphné; Garrido, M del R; Lamb, Andrew; Hénon, Clémence; Dorvault, Nicolas; Rouanne, Mathieu; Marlow, Rebecca; Bajrami, Ilirjana; Cardenosa, Marta Llorca; Konde, Asha; Besse, Benjamin; Ashworth, Alan; Pettitt, Stephen J.; Haider, Syed; Marabelle, Aurélien; Tutt, Andrew; Soria, Jean‐Charles; Lord, Christopher J.; Postel-Vinay, Sophie

doi:10.1172/jci123319

Cited by 227 publications

(159 citation statements)

References 55 publications

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“…In the same context, inactivation of replicative stress response factors (PARP1 and/or ATR inhibition) enhances the cGAS-STING-mediated interferon response after BRCA2 inactivation in human cell lines [74,244]. Similar results have been shown in small cell lung cancer (SCLC) after the inhibition of either PARP1 or CHK1 [245,246].…”

Section: Implications For Immunotherapysupporting

confidence: 58%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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Section: Implications For Immunotherapysupporting

confidence: 58%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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“…Radiotherapy or chemotherapy drugs such as cisplatin or cyclophosphamide can induce DSBs and micronuclei, then trigger the cGAS-STING pathway to enhance tumor immunogenicity (252)(253)(254). In addition, PARP inhibitors such as olaparib have promising effects on cancer cells lacking BRCA2 because of their cooperative DNA-repair functions (253).…”

Section: Targeting the Cgas-sting Pathway For Treatmentmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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“…PARPi are thought to induce DNA damage that leads to double strand breaks in homologous recombination deficient tumor cells that cannot properly repair the DNA damage . Homologous repair‐deficient tumor cells treated with PARPi in vitro induced cytosolic DNA that lead to STING signaling demonstrated by TBK1 and IRF3 phosphorylation . Both of these phosphorylation events were reduced after siRNA knockdown of cGAS or STING.…”

Section: Sting Pathway Involvement In Anti‐tumor Immunity In Preclinimentioning

confidence: 99%

“…130 Homologous repair-deficient tumor cells treated with PARPi in vitro induced cytosolic DNA that lead to STING signaling demonstrated by TBK1 and IRF3 phosphorylation. [131][132][133] Both of these phosphorylation events were reduced after siRNA knockdown of cGAS or STING. When PARPi were used to treat mouse ovarian tumors, cotreatment with a TBK1 inhibitor abolished efficacy, suggesting that STING signaling was required for efficacy in this model.…”

Section: Indirect Sting Activation By Other Cancer Therapiesmentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

205

161

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The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

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PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer

Cited by 227 publications

References 55 publications

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

STING pathway agonism as a cancer therapeutic

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