American Association for Cancer Research
23266066cir210224-sup-262699_3_video_7413162_qzscl2.mp4 (5.67 MB)

Video 3 from BET Inhibition Enhances TNF-Mediated Antitumor Immunity

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posted on 2023-04-04, 01:26 authored by Lisa C. Wellinger, Simon J. Hogg, Dane M. Newman, Thomas Friess, Daniela Geiss, Jessica Michie, Kelly M. Ramsbottom, Marina Bacac, Tanja Fauti, Daniel Marbach, Laura Jarassier, Phillip Thienger, Axel Paehler, Leonie A. Cluse, Conor J. Kearney, Stephin J. Vervoort, Joseph A. Trapani, Jane Oliaro, Jake Shortt, Astrid Ruefli-Brasse, Daniel Rohle, Ricky W. Johnstone

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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 epigenetics-based 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-κB target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of prosurvival NF-κB signaling by BETi led to unrestrained TNF-mediated 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.