1. BET Inhibition Enhances TNF-Mediated Anti-Tumor Immunity.
- Author
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Wellinger L.C., Hogg S.J., Newman D.M., Friess T., Geiss D., Michie J., Ramsbottom K.M., Bacac M., Fauti T., Marbach D., Jarassier L., Thienger P., Paehler A., Cluse L.A., Kearney C.J., Vervoort S.J., Trapani J.A., Oliaro J., Shortt J., Ruefli-Brasse A., Rohle D., Johnstone R.W., Wellinger L.C., Hogg S.J., Newman D.M., Friess T., Geiss D., Michie J., Ramsbottom K.M., Bacac M., Fauti T., Marbach D., Jarassier L., Thienger P., Paehler A., Cluse L.A., Kearney C.J., Vervoort S.J., Trapani J.A., Oliaro J., Shortt J., Ruefli-Brasse A., Rohle D., and Johnstone R.W.
- Abstract
Targeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance anti-tumor 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 anti-tumor activity of CD8+ T cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the pro-inflammatory 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 pro-survival 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.Copyright ©2021, American Association for Cancer Research.
- Published
- 2022