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BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [ChIP-Seq, ATAC-Seq]

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 bromodomain 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-B target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of pro-survival NF-B 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 (TCB) antibodies 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE184591 | GEO | 2021/09/24

REPOSITORIES: GEO

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BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [RNA-Seq]

Project description: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 bromodomain 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-B target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of pro-survival NF-B 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 (TCB) antibodies 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.

2021-09-24 | GSE184589 | GEO

Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma (Affy SNP6.0 Arrays)

Project description:Chronic active B cell receptor (BCR) signaling, a hallmark of the ABC subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activates IkappaB kinase (IKK) and the classical NF-kappaB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-kappaB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetic drugs target cIAP1/2 for destruction, and consequently suppress NF-kappaB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL. Four ABC DLBCL tumor biopsy samples and one ABC DLBCL cell line (YM) (n=5) were analysed for copy number gains using the Affymetrix Genome-Wide Human SNP 6.0 Array. CEL files are being made available through dbGaP

2016-09-01 | E-GEOD-73639 | biostudies-arrayexpress

cIAP1/2 antagonism induces antigen-specific T cell dependent immunity

Project description:Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naïve T cells can receive co-stimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cIAP1/2, also called SMAC mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics co-stimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Here, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell-dependent anti-tumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

2023-01-25 | GSE222095 | GEO

Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma (Agilent Arrays)

Project description:Chronic active B cell receptor (BCR) signaling, a hallmark of the ABC subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activates IkappaB kinase (IKK) and the classical NF-kappaB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-kappaB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetic drugs target cIAP1/2 for destruction, and consequently suppress NF-kappaB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL. Samples from four ABC DLBCL cell lines (HBL1, TMD8, OCILY3, and OCILY10) were exposed to 2.5 uM birinapant for 2, 4, 6, and 24 hours (n=16). Samples from 2 ABC DLBCL cell lines (HBL1 and TMD8) were transduced with shRNA and induced with doxycycline for 3 and 4 days (n=4).

2016-09-01 | E-GEOD-73281 | biostudies-arrayexpress

Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma (Affy SNP6.0 Arrays)

2016-09-01 | GSE73639 | GEO

Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma (Agilent Arrays)

2016-09-01 | GSE73281 | GEO

NFkB in multiple myeloma - EJM IkBa super-repressor

Project description:Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta), targeting the classical NF-kappaB pathway, was lethal to many myeloma cell lines. Several had elevated expression of NIK due to genomic alterations or enhanced protein stability while others had inactivating mutations or deletion of TRAF3. Both abnormalities triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic and epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, and NFKB2. These genetic and functional data demonstrate that addiction to the NF-kappaB pathway is a frequent feature of myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease. Keywords: time series design

2007-10-29 | GSE8477 | GEO

NFkB in multiple myeloma - L363 IKK inhibitor

2007-10-29 | GSE8476 | GEO

Inhibitor of apoptosis proteins as promising therapeutic targets in chronic lymphocytic leukemia

Project description:Inhibitor of apoptosis (IAP) proteins are expressed at high levels in CLL cells and may contribute to evasion of cell death leading to poor therapeutic outcome. Of note, prognostic unfavourable cases with e.g. non-mutated VH-status and TP53 mutation responded significantly better to BV6 than samples with unknown or favourable prognosis e.g. 13q deletion. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases were sensitive to BV6, indicating that BV6 acts independently of the p53 pathway. Importantly, BV6 dose-dependently induced cell death in 28 of 51 (54%) investigated patient samples while B cells from healthy donors were largely unaffected. BV6 also triggered cell death under survival conditions mimicking the microenvironment e.g. by adding CD40 ligand or in conditioned medium. Gene expression profiling identified cell death- and NF-kB-signaling among the top pathways regulated by BV6. This was confirmed by data showing that BV6 causes degradation of cIAP1 and cIAP2 and NF-kB pathway activation. BV6 induced cell death depended on production of reactive oxygen species, since addition of ROS scavengers significantly rescued BV6-triggerd cell death. In contrast, BV6 induced cell death independently of caspase activity, RIP1 activity or TNF-alpha, since zVAD.fmk, necrostatin-1 or TNF-alpha-blocking antibody Enbrel failed to protect against cell death. Of note, transcripts of ROS regulatory proteins were modulated by BV6. Thus, these data have important implications for developing new therapeutic strategies to overcome cell death resistance in CLL especially in poor prognostic subgroups. Gene expression was profiled in 12 CLL samples [n=3 CLL cases for 4 hours and 20 hours with either DMSO or BV6].

2015-03-31 | E-GEOD-62533 | biostudies-arrayexpress

Pan-cancer bioinformatics analysis of TNFRSF12A and functional study in colorectal cancer

Project description:Cancer has become a major public health problem in the world, however challenges such as drug resistance, metastasis and cancer recurrence continue to be unresolved issues. Therefore, it is important to find new cancer markers or therapeutic targets. Tn this study, we found TNF receptor superfamily member 12A (TNFRSF12A) upregulated in cancer and associated with a poor prognosis. TNFRSF12A knockdown inhibited growth, colony formation and migration of colorectal cancer cells, and overexpression TNFRSF12A promoted these behaviors of colorectal cancer cells. RNA-seq results showed that TNFRSF12A overexpression caused increased NF-κB signaling, transcriptional misregulation, and significant upregulation of BIRC3 gene, which may be the transcription target of NF-κB member RELA. Through BIRC3 knockdown in overexpressed TNFRSF12A cells, we proved BIRC3 is a key downstream of TNFRSF12A. Therefore, we speculated the existance of TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer.

2024-03-13 | GSE261177 | GEO

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