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

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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_745449157CA6
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING.
Journal
Cell reports
Author(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)
Publication state
Published
Issued date
20/07/2021
Peer-reviewed
Oui
Volume
36
Number
3
Pages
109412
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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.
Keywords
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
Yes
Create date
26/07/2021 9:17
Last modification date
10/08/2021 7:10
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