Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING.

Détails

Ressource 1Télécharger: 1-s2.0-S2211124721008251-main.pdf (9618.38 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY-NC-ND 4.0
ID Serval
serval:BIB_745449157CA6
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Synthèse (review): revue aussi complète que possible des connaissances sur un sujet, rédigée à partir de l'analyse exhaustive des travaux publiés.
Collection
Publications
Institution
Titre
Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING.
Périodique
Cell reports
Auteur(s)
Bruand M., Barras D., Mina M., Ghisoni E., Morotti M., Lanitis E., Fahr N., Desbuisson M., Grimm A., Zhang H., Chong C., Dagher J., Chee S., Tsianou T., Dorier J., Stevenson B.J., Iseli C., Ronet C., Bobisse S., Genolet R., Walton J., Bassani-Sternberg M., Kandalaft L.E., Ren B., McNeish I., Swisher E., Harari A., Delorenzi M., Ciriello G., Irving M., Rusakiewicz S., Foukas P.G., Martinon F., Dangaj Laniti D., Coukos G.
ISSN
2211-1247 (Electronic)
Statut éditorial
Publié
Date de publication
20/07/2021
Peer-reviewed
Oui
Volume
36
Numéro
3
Pages
109412
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1 <sup>mut</sup> ) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1 <sup>mut</sup> cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8 <sup>+</sup> T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53 <sup>-/-</sup> Brca1 <sup>-/-</sup> but not Brca1 <sup>+/+</sup> ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.
Mots-clé
BRCA1, CTLA-4, DNA sensing, ICB, PARPi, PD-L1, STING, T cells, VEGF-A, angiogenesis, dual immune checkpoint blockade, ovarian cancer, type I IFN
Pubmed
Web of science
Open Access
Oui
Création de la notice
26/07/2021 8:17
Dernière modification de la notice
25/10/2021 17:50
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