BET Inhibition Enhances TNF-Mediated Antitumor Immunity
| Autor: | Tanja Fauti, Lisa Wellinger, Joseph A. Trapani, Axel Paehler, Daniela Geiss, Kelly M Ramsbottom, Laura Jarassier, Phillip Thienger, Leonie A. Cluse, Conor J. Kearney, Thomas Friess, Stephin J. Vervoort, Jane Oliaro, Daniel Rohle, Ricky W. Johnstone, Marina Bacac, Simon J. Hogg, Astrid Ruefli-Brasse, Dane M. Newman, Daniel Marbach, Jake Shortt, Jessica Michie |
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| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
Ubiquitin-Protein Ligases medicine.medical_treatment Immunology Antineoplastic Agents Apoptosis Cell Cycle Proteins CD8-Positive T-Lymphocytes Inhibitor of Apoptosis Proteins Immune system Cell Line Tumor medicine Animals Humans Cytotoxic T cell Cell Proliferation Chemistry Chromatin binding NF-kappa B Nuclear Proteins Immune checkpoint Gene Expression Regulation Neoplastic Cytokine Cancer research Tumor necrosis factor alpha Colorectal Neoplasms CD8 Signal Transduction Transcription Factors |
| Zdroj: | Cancer Immunology Research. 10:87-107 |
| ISSN: | 2326-6074 2326-6066 |
| DOI: | 10.1158/2326-6066.cir-21-0224 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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