@article{457e1873de8f45b2940a568b7fba0e09,
title = "BET Inhibition Enhances TNF-Mediated Antitumor Immunity",
abstract = "Targeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance antitumor immunity and augment cancer immunotherapies. By screening a small-molecule library of epigeneticsbased therapeutics, BET (bromo- and extra-terminal domain) inhibitors (BETi) were identified as agents that sensitize tumor cells to the antitumor activity of CD8 T cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the proinflammatory cytokine TNF. By preventing the recruitment of BRD4 to p65-bound cis-regulatory elements, BETi suppressed the induction of inflammatory gene expression, including the key NF-kB target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of prosurvival NF-kB signaling by BETi led to unrestrained TNFmediated activation of the extrinsic apoptotic cascade and tumor cell death. Administration of BETi in combination with T-cell bispecific antibodies (TCB) or immune-checkpoint blockade increased bystander killing of tumor cells and enhanced tumor growth inhibition in vivo in a TNF-dependent manner. This novel epigenetic mechanism of immunomodulation may guide future use of BETi as adjuvants for immune-oncology agents.",
author = "Wellinger, {Lisa C.} and Hogg, {Simon J.} and Newman, {Dane M.} and Thomas Friess and Daniela Geiss and Jessica Michie and Ramsbottom, {Kelly M.} and Marina Bacac and Tanja Fauti and Daniel Marbach and Laura Jarassier and Phillip Thienger and Axel Paehler and Cluse, {Leonie A.} and Kearney, {Conor J.} and Vervoort, {Stephin J.} and Trapani, {Joseph A.} and Jane Oliaro and Jake Shortt and Astrid Ruefli-Brasse and Daniel Rohle and Johnstone, {Ricky W.}",
note = "Funding Information: The authors thank Dr. Vignesh Narasimhan and Prof. Robert Ramsay (Peter MacCallum Cancer Centre, Melbourne, Australia) for assistance with patient-derived colorectal tumoroid cultures. They thank Prof. John Silke (Walter and Eliza Hall Institute, Melbourne, Australia) and members of the Johnstone Laboratory for helpful discussions. The laboratory of R.W. Johnstone was supported by the Cancer Council of Victoria, National Health and Medical Research Council of Australia (NHMRC), and The Kids{\textquoteright} Cancer Project (R.W. Johnstone). S.J. Hogg was supported by a Postdoctoral Fellowship from the Cancer Council of Victoria. The Peter MacCallum Foundation and Australian Cancer Research Foundation provided generous support for equipment and core facilities. Funding Information: L.C. Wellinger reports a patent for WO 2020/169698 A1 issued. S.J. Hogg reports grants from Cancer Council of Victoria during the conduct of the study, as well as a patent for combination therapy of bromodomain inhibitors and checkpoint blockade (WO2017059319A2) licensed and with royalties paid from F. Hoffmann-La Roche AG and a patent for sensitization of cancer cells to TNF by BET inhibition (WO2020169698A1) pending to F. Hoffmann-La Roche AG. T. Friess reports a patent for 20210023099 issued, a patent for 20200237905 issued, and a patent for 20200237779 issued. M. Bacac reports a patent for 20180282410 issued and a patent for WO/2020/169698 issued. T. Fauti reports a patent for WO 2020/169698 A1 issued. J. Oliaro reports grants from National Health and Medical Research Council of Australia and National Breast Cancer Foundation during the conduct of the study, as well as grants from National Health and Medical Research Council of Australia and National Breast Cancer Foundation outside the submitted work. J. Shortt reports personal fees from Astellas and Novartis, and grants from Bristol Myers Squibb, Amgen, and Astex outside the submitted work, as well as a patent for WO2107059319A2 licensed and with royalties paid from Roche. A. Ruefli-Brasse reports a patent for 20210023099 pending to Roche, a patent for 20200237905 pending to Roche, and a patent for 20200237779 pending to Roche. D. Rohle reports a patent for WO 2020/169698 A1 issued. R.W. Johnstone reports grants from Roche during the conduct of the study; grants from Bristol Myers Squibb and AstraZeneca, and grants and personal fees from MycRx outside the submitted work; and a patent for WO2017059319A2 licensed to R.W. Johnstone, S.J. Hogg, and J. Shortt. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research Inc.. All rights reserved.",
year = "2022",
month = jan,
doi = "10.1158/2326-6066.CIR-21-0224",
language = "English",
volume = "10",
pages = "87--107",
journal = "Cancer Immunology Research",
issn = "2326-6066",
publisher = "American Association for Cancer Research (AACR)",
number = "1",
}