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BET Inhibition Enhances TNF-Mediated Antitumor Immunity
Lisa C Wellinger1, Simon J Hogg2,3, Dane M Newman2
1Roche Pharma Research and Early Development, Oncology Discovery, Roche Innovation Center Basel, Basel, Switzerland.
Cancer Immunology Research
|November 16, 2021
Summary
BET inhibitors (BETi) enhance cancer immunotherapies by sensitizing tumor cells to T cell activity and TNF-induced apoptosis. This epigenetic approach improves tumor growth inhibition when combined with T-cell bispecific antibodies or immune-checkpoint blockade.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Targeting chromatin proteins and enzymes impacts tumor cell proliferation, survival, and immune response.
- Epigenetic therapies offer potential for augmenting cancer immunotherapies.
Purpose of the Study:
- To identify epigenetic agents that enhance antitumor immunity.
- To investigate the mechanism by which BET inhibitors sensitize tumor cells to T cell-mediated cytotoxicity and TNF.
Main Methods:
- Screening of a small-molecule library for epigenetics-based therapeutics.
- Assessing the effects of BET inhibitors on tumor cell sensitization to CD8+ T cells and TNF.
- Investigating the molecular mechanisms involving BRD4, NF-κB signaling, and apoptotic pathways.
- Evaluating the efficacy of BET inhibitors in combination with T-cell bispecific antibodies or immune-checkpoint blockade in vivo.
Main Results:
- BET inhibitors (BETi) were identified as agents sensitizing tumor cells to CD8+ T cell antitumor activity.
- BETi induced tumor cell sensitization to the cytotoxic effects of TNF.
- BETi suppressed inflammatory gene expression by preventing BRD4 recruitment to p65-bound cis-regulatory elements, including NF-κB target genes BIRC2 and BIRC3.
- Disruption of prosurvival NF-κB signaling by BETi led to TNF-mediated apoptosis and tumor cell death.
- Combination therapy with BETi and TCB or immune-checkpoint blockade enhanced bystander killing and tumor growth inhibition in a TNF-dependent manner.
Conclusions:
- BET inhibitors represent a novel epigenetic mechanism for immunomodulation.
- BETi can sensitize tumor cells to immune-mediated killing and apoptosis.
- This approach may guide the future use of BET inhibitors as adjuvants in immune-oncology treatments.
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