BET Inhibition Enhances TNF-Mediated Antitumor Immunity

Wellinger, LC; Hogg, SJ; Newman, DM; Friess, T; Geiss, D; Michie, J; Ramsbottom, KM; Bacac, M; Fauti, T; Marbach, D; Jarassier, L; Thienger, P; Paehler, A; Cluse, LA; Kearney, CJ; Vervoort, SJ; Trapani, JA; Oliaro, J; Shortt, J; Ruefli-Brasse, A; Rohle, D; Johnstone, RW

Author(s): Wellinger, LC; Hogg, SJ; Newman, DM; Friess, T; Geiss, D; Michie, J; Ramsbottom, KM; Bacac, M; Fauti, T; Marbach, D; Jarassier, L; Thienger, P; Paehler, A; Cluse, LA; Kearney, CJ; Vervoort, SJ; Trapani, JA; Oliaro, J; Shortt, J; Ruefli-Brasse, A; Rohle, D; Johnstone, RW;
Details: Publication Year 2022-01,Volume 10,Issue #1,Page 87-107
Journal Title: Cancer Immunology Research
Publication Type: Research article
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 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-kappaB target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of prosurvival NF-kappaB 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.
Keywords: Animals; Antineoplastic Agents/*administration & dosage; Apoptosis/drug effects; CD8-Positive T-Lymphocytes/metabolism; Cell Cycle Proteins/genetics/metabolism; Cell Line, Tumor; Cell Proliferation/drug effects; Colorectal Neoplasms/*drug therapy/genetics/metabolism; Gene Expression Regulation, Neoplastic/drug effects; Humans; Inhibitor of Apoptosis Proteins/*genetics/metabolism; NF-kappa B/metabolism; Nuclear Proteins/*antagonists & inhibitors/genetics/metabolism; Signal Transduction/drug effects; Transcription Factors/genetics/metabolism; Ubiquitin-Protein Ligases/*genetics/metabolism
Department(s): Laboratory Research
PubMed ID: 34782346
Publisher's Version: https://doi.org/10.1158/2326-6066.CIR-21-0224
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-09 06:08:25

Last Modified: 2025-05-09 06:09:24