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CIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

ABSTRACT: Induction of non-canonical NF-kB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We show that induction of non-canonical NF-kB signaling induces T-cell dependent immune responses even in B2M-null tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced cytokines reprogram macrophages to be tumoricidal. In wildtype mice, IAP antagonism reduces tumor burden by increasing phagocytosis of tumor cells. We characterized by RNA-Seq the transcriptional response of macrophages to T-cell produced lymphotoxin (LT) in the presence or absence of the IAP antagonist LCL161.

ORGANISM(S): Mus musculus

PROVIDER: GSE150269 | GEO | 2021/04/30

REPOSITORIES: GEO

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cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Project description:Induction of non-canonical NF-kB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We now show that induction of non-canonical NF-kB signaling induces T-cell dependent immune responses even in B2M-null tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced cytokines reprogram macrophages to be tumoricidal. In wildtype mice IAP antagonism reduces tumor burden by increasing phagocytosis of tumor cells. We characterized by RNA-Seq the transcriptional profile of intratumoral phagocytes with and without treatment with the IAP antagonist LCL161.

2021-04-30 | GSE150270 | GEO

cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Project description:Induction of non-canonical NF-kB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We show that induction of non-canonical NF-kB signaling induces T-cell dependent immune responses even in B2M-null tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced cytokines reprogram macrophages to be tumoricidal. We characterized by single-cell RNA-Seq the transcriptional profile of immune cells infilitrating mouse pancreatic tumors treated with the IAP anatagonist LCL161.

2021-04-30 | GSE150271 | GEO

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GSK-3alpha Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Non-Canonical NF-kB

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Project description:The inhibitor of kB kinase (IKK) is the master regulator of the nuclear factor kB (NF-kB) pathway, involved in inflammatory, immune and apoptotic responses. In the ‘canonical’ NF-kB pathway, IKK phosphorylates inhibitor of kB (IkB) proteins and this triggers ubiquitin-mediated degradation of IkB, leading to release and nuclear translocation of NF-B transcription factors. The data presented show that the IKK and IKK subunits recognize a YDDX docking site located within the disordered C-terminal region of IkBa. Our results also suggest that IKK contributes to the docking interaction with higher affinity as compared to IKK.

2024-05-09 | PXD037534 | JPOST Repository

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Project description:NF-kappaB Activation Model includes the activation of both NFKB1:RELA and NFKB2:RELB for Canonical and Non-Canonical Pathway respectively. The model includes the pathway model integrated with post-translational modifications of NF-kB subunits that regulate the NFKB1:RELA and NFKB2:RELB activity. The processes that are regulated by NF-kB pathway can be monitored through following readouts NFKB1:RELA Activity, NFKB2:RELB Activity, Degraded RelA, Degraded RelB, Degraded IkB, Degraded NIK, Apoptosis, Tumour, Antiviral Activity, B Cell Growth and Cell Migration. However, last 5 processes above are also influenced by other pathways too, therefore while making predictions, caution has to be exercised.

2022-05-27 | MODEL2001290001 | BioModels

IkB-like protein NFKBIZ regulates NF-kB signaling and is critical for survival of ABC DLBCL (NFKBIZ inhibition)

Project description:Constitutive activation of the nuclear factor-kappa B (NF-kB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the IkB-like protein NFKBIZ that binds NF-kB subunits and enhances transactivation of some NF-kB target genes while repressing others, to be upregulated in ACB compared to GCB DLBCL primary patient samples (p=5.1 x 10^-37). Knockdown of NFKBIZ by RNA interference was toxic to ABC but not GCB DLBCL cell lines. Gene expression profiling following NFKBIZ knockdown significantly downregulated a large number of NF-kB target genes, suggesting a central role in regulating NF-kB signaling. To further investigate the molecular mechanisms of how NFKBIZ mediates NF-kB signaling in ABC DLBCL, we performed immunoprecipitations and detected an interaction of NFKBIZ with both p50 and p52 NF-kB subunits, indicating that both the canonical and non-canonical NF-kB pathways are regulated by NFKBIZ. Collectively, our data imply that NFKBIZ is required for NF-kB signaling in ABC DLBCL and thus might represent a promising molecular target for future therapies. The complete dataset is comprised of three experiments with the male HBL-1 ABC DLBCL cell line: a) 8 paired GEP measurements after NFKBIZ inhibition by shRNA, b) 6 paired GEP measurements after applying the MLN inhibitor and c) 4 two-color measurements after applying a MALT inhibitor. This dataset includes 8 paired GEP measurements after NFKBIZ inhibition by shRNA.

2013-07-22 | E-GEOD-46971 | biostudies-arrayexpress

IkB-like protein NFKBIZ regulates NF-kB signaling and is critical for survival of ABC DLBCL (MLN inhibition)

Project description:Constitutive activation of the nuclear factor-kappa B (NF-kB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the IkB-like protein NFKBIZ that binds NF-kB subunits and enhances transactivation of some NF-kB target genes while repressing others, to be upregulated in ACB compared to GCB DLBCL primary patient samples (p=5.1 x 10^-37). Knockdown of NFKBIZ by RNA interference was toxic to ABC but not GCB DLBCL cell lines. Gene expression profiling following NFKBIZ knockdown significantly downregulated a large number of NF-kB target genes, suggesting a central role in regulating NF-kB signaling. To further investigate the molecular mechanisms of how NFKBIZ mediates NF-kB signaling in ABC DLBCL, we performed immunoprecipitations and detected an interaction of NFKBIZ with both p50 and p52 NF-kB subunits, indicating that both the canonical and non-canonical NF-kB pathways are regulated by NFKBIZ. Collectively, our data imply that NFKBIZ is required for NF-kB signaling in ABC DLBCL and thus might represent a promising molecular target for future therapies. The complete dataset is comprised of three experiments with the male HBL-1 ABC DLBCL cell line: a) 8 paired GEP measurements after NFKBIZ inhibition by shRNA, b) 6 paired GEP measurements after applying the MLN inhibitor and c) 4 two-color measurements after applying a MALT inhibitor. This dataset includes 6 paired GEP measurements after applying the MLN inhibitor.

2013-07-22 | E-GEOD-46972 | biostudies-arrayexpress

IkB-like protein NFKBIZ regulates NF-kB signaling and is critical for survival of ABC DLBCL (MALT inhibition)

Project description:Constitutive activation of the nuclear factor-kappa B (NF-kB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the IkB-like protein NFKBIZ that binds NF-kB subunits and enhances transactivation of some NF-kB target genes while repressing others, to be upregulated in ACB compared to GCB DLBCL primary patient samples (p=5.1 x 10^-37). Knockdown of NFKBIZ by RNA interference was toxic to ABC but not GCB DLBCL cell lines. Gene expression profiling following NFKBIZ knockdown significantly downregulated a large number of NF-kB target genes, suggesting a central role in regulating NF-kB signaling. To further investigate the molecular mechanisms of how NFKBIZ mediates NF-kB signaling in ABC DLBCL, we performed immunoprecipitations and detected an interaction of NFKBIZ with both p50 and p52 NF-kB subunits, indicating that both the canonical and non-canonical NF-kB pathways are regulated by NFKBIZ. Collectively, our data imply that NFKBIZ is required for NF-kB signaling in ABC DLBCL and thus might represent a promising molecular target for future therapies. The complete dataset is comprised of three experiments with the male HBL-1 ABC DLBCL cell line: a) 8 paired GEP measurements after NFKBIZ inhibition by shRNA, b) 6 paired GEP measurements after applying the MLN inhibitor and c) 4 two-color measurements after applying a MALT inhibitor. This dataset includes 4 two-color measurements of the male HBL-1 ABC DLBCL cell line after applying a MALT inhibitor.

2013-07-22 | E-GEOD-46973 | biostudies-arrayexpress

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