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

Marine Bruand; David Barras; Marco Mina; Eleonora Ghisoni; Matteo Morotti; Evripidis Lanitis; Noémie Fahr; Mathieu Desbuisson; Alizée Grimm; Hualing Zhang; Chloe Chong; Julien Dagher; Sora Chee; Theodora Tsianou; Julien Dorier; Brian J Stevenson; Christian Iseli; Catherine Ronet; Sara Bobisse; Raphael Genolet; Josephine Walton; Michal Bassani-Sternberg; Lana E Kandalaft; Bing Ren; Iain McNeish; Elizabeth Swisher; Alexandre Harari; Mauro Delorenzi; Giovanni Ciriello; Melita Irving; Sylvie Rusakiewicz; Periklis G Foukas; Fabio Martinon; Denarda Dangaj Laniti; George Coukos

doi:10.1016/j.celrep.2021.109412

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

Cell Rep. 2021 Jul 20;36(3):109412. doi: 10.1016/j.celrep.2021.109412.

Authors

Marine Bruand¹, David Barras², Marco Mina³, Eleonora Ghisoni¹, Matteo Morotti¹, Evripidis Lanitis¹, Noémie Fahr¹, Mathieu Desbuisson¹, Alizée Grimm¹, Hualing Zhang⁴, Chloe Chong¹, Julien Dagher⁵, Sora Chee⁶, Theodora Tsianou¹, Julien Dorier⁷, Brian J Stevenson⁸, Christian Iseli⁸, Catherine Ronet¹, Sara Bobisse¹, Raphael Genolet¹, Josephine Walton⁹, Michal Bassani-Sternberg¹, Lana E Kandalaft¹, Bing Ren⁶, Iain McNeish⁹, Elizabeth Swisher¹⁰, Alexandre Harari¹, Mauro Delorenzi², Giovanni Ciriello³, Melita Irving¹, Sylvie Rusakiewicz¹, Periklis G Foukas¹¹, Fabio Martinon¹², Denarda Dangaj Laniti¹³, George Coukos¹⁴

Affiliations

¹ Ludwig Institute for Cancer Research, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
² Ludwig Institute for Cancer Research, University Hospital of Lausanne (CHUV), Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
³ Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Computational Biology, UNIL, Lausanne, Switzerland.
⁴ Ludwig Institute for Cancer Research, University Hospital of Lausanne (CHUV), Lausanne, Switzerland; Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China.
⁵ Institute of Pathology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
⁶ Ludwig Institute for Cancer Research and University of California, La Jolla, CA, USA.
⁷ Swiss Institute of Bioinformatics, Lausanne, Switzerland; Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland.
⁸ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁹ Department of Surgery & Cancer, Ovarian Cancer Action Research Centre, Hammersmith Hospital, Imperial College London, London, UK.
¹⁰ Department of Oncology, Washington University, Seattle, WA, USA.
¹¹ 2nd Department of Pathology, Attikon Hospital, National and Kapodistrian University of Athens, Athens, Greece.
¹² Department of Biochemistry, UNIL, Lausanne, Switzerland.
¹³ Ludwig Institute for Cancer Research, University Hospital of Lausanne (CHUV), Lausanne, Switzerland. Electronic address: denarda.dangaj@chuv.ch.
¹⁴ Ludwig Institute for Cancer Research, University Hospital of Lausanne (CHUV), Lausanne, Switzerland. Electronic address: george.coukos@chuv.ch.

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^mut) 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^mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8⁺ 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^-/-Brca1^-/- but not Brca1^+/+ 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
BRCA1 Protein / deficiency*
BRCA1 Protein / metabolism
Cell Line, Tumor
Chemokine CCL5 / metabolism
Chromatin / metabolism
DNA / metabolism
DNA Damage
Epigenesis, Genetic
Female
Gene Silencing
Humans
Immune Checkpoint Inhibitors / pharmacology
Inflammation / complications
Inflammation / immunology
Inflammation / pathology*
Interferons / metabolism
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Neoplasm Grading
Neovascularization, Pathologic / pathology
Ovarian Neoplasms / complications
Ovarian Neoplasms / genetics
Ovarian Neoplasms / immunology*
Ovarian Neoplasms / pathology*
Protein Serine-Threonine Kinases / metabolism
T-Lymphocytes / immunology
Transcription, Genetic
Vascular Endothelial Growth Factor A / metabolism

Substances

BRCA1 Protein
BRCA1 protein, human
Chemokine CCL5
Chromatin
Immune Checkpoint Inhibitors
Membrane Proteins
STING1 protein, human
Vascular Endothelial Growth Factor A
DNA
Interferons
Protein Serine-Threonine Kinases
TBK1 protein, human

Grants and funding

P50 CA083638/CA/NCI NIH HHS/United States