SP-0258: Potentiation of anti-tumor immune effects by PARP Inhibitors

Chabanon, R; Muirhead, Gareth; Krastev, Dimo; Adam, Julien; Garrido, M del R; Morel, Daphné; Dorvault, Nicolas; Pettitt, Stephen J.; Tutt, Andrew N.J.; Marabelle, Aurélien; Soria, J; Lord, Christopher J.; Postel-Vinay, S.

doi:10.1016/s0167-8140(21)00282-6

Cited by 1 publication

(5 citation statements)

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“…We and others previously described that PARPi have cell-autonomous immunomodulatory properties, which activate the cGAS/STING signaling cascade in DDR-defective genetic contexts (23,43,44,61). However, very little is known about the immunomodulatory properties of ATRi.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were then fixed in 4% paraformaldehyde for 20 min at RT, washed twice with PBS, and permeabilized with 0.2% Triton X-100 in PBS for 10 min. Subsequent labeling, imaging and image analysis steps were performed as previously described (23).…”

Section: Immunofluorescence and Image Analysismentioning

confidence: 99%

“…The cytosolic DNA sensing cyclic GMP-AMP synthase / stimulator of interferon genes (cGAS/STING) pathway detects cytosolic DNA (often the by-product of viral infection, DNA damage or replication stress) and in turn activates type I interferon innate immune signaling (42). PARPi-induced activation of cGAS/STING following micronuclei formation and the generation of cytosolic DNA, is now recognized as an important component of PARPi-mediated synthetic lethal effects (23,(43)(44)(45). Recent reports also suggest that R-loops may contribute to cGAS/STING activation (40,46).…”

Section: Parp and Atr Inhibitors Induce A Cell-autonomous Cgas/sting ...mentioning

confidence: 99%

“…Moreover, the cGAS/STING pathway plays an essential role in the therapeutic effect of immune checkpoint inhibitors (ICI) (47,48), a standard-of-care in ccRCC and NSCLC, two histologies where PBRM1 is frequently mutated. Given this, we assessed whether PARPi or ATRi activated cGAS/STING signaling in PBRM1defective ccRCC and NSCLC cells, as PARPi are known to do in BRCA-mutant tumor cells (23,45,49). To assess this, we measured three sequentially-occurring phenotypes that are linked to PARPi-mediated cGAS/STING pathway activation and anti-tumor immunity: (i) the accumulation of cytosolic DNA in the form of micronuclei;…”

Section: Parp and Atr Inhibitors Induce A Cell-autonomous Cgas/sting ...mentioning

confidence: 99%

“…(ii) the phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3); (iii) the induction of a type I interferon response (23,43,44).…”

Section: Parp and Atr Inhibitors Induce A Cell-autonomous Cgas/sting ...mentioning

confidence: 99%

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PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Section: Immunofluorescence and Image Analysismentioning

confidence: 99%

Section: Parp and Atr Inhibitors Induce A Cell-autonomous Cgas/sting ...mentioning

confidence: 99%

Section: Parp and Atr Inhibitors Induce A Cell-autonomous Cgas/sting ...mentioning

confidence: 99%

“…(ii) the phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3); (iii) the induction of a type I interferon response (23,43,44).…”

Section: Parp and Atr Inhibitors Induce A Cell-autonomous Cgas/sting ...mentioning

confidence: 99%

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