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

Author

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., and Martinon, F.

Subjects
BRCA1, CTLA-4, DNA sensing, ICB, PARPi, PD-L1, STING, T cells, VEGF-A, angiogenesis, dual immune checkpoint blockade, ovarian cancer, type I IFN
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.

Published
2021

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

Author

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 BJ, Iseli C, Ronet C, Bobisse S, Genolet R, Walton J, Bassani-Sternberg M, Kandalaft LE, Ren B, McNeish I, Swisher E, Harari A, Delorenzi M, Ciriello G, Irving M, Rusakiewicz S, Foukas PG, Martinon F, Dangaj Laniti D, and Coukos G

Subjects
Animals, 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, Interferons metabolism, Mice, Inbred C57BL, Neoplasm Grading, Neovascularization, Pathologic pathology, Ovarian Neoplasms complications, Ovarian Neoplasms genetics, Protein Serine-Threonine Kinases metabolism, T-Lymphocytes immunology, Transcription, Genetic, Vascular Endothelial Growth Factor A metabolism, Mice, BRCA1 Protein deficiency, Inflammation pathology, Membrane Proteins metabolism, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology
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., Competing Interests: Declaration of interests G. Coukos has received grants from Celgene, Boehringer-Ingelheim, Roche, BMS, Iovance Therapeutics, and Kite Pharma. The institution G. Coukos is affiliated with has received fees for G. Coukos’ participation on an advisory board or for presentation at a company-sponsored symposium from Genentech, Roche, BMS, AstraZeneca, NextCure, Geneos Tx, and Sanofi/Avensis. G. Coukos has patents in the domain of antibodies and vaccines targeting the tumor vasculature as well as technologies related to T cell expansion and engineering for T cell therapy. G. Coukos holds patents around antibodies and receives royalties from the University of Pennsylvania regarding technology licensed to Novartis. The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2021
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