SPP1+ Neutrophils Mediate Resistance to lmmune Checkpoint Blockade in BAP1-Inactivated Tumors
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PROVIDER: PRJNA1198010 | ENA |
REPOSITORIES: ENA
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Project description:BAP1 inactivation, observed across multiple human cancers, is linked to immune checkpoint blockade (ICB) resistance and adverse clinical outcomes. The mechanisms underlying BAP1-associated ICB sensitivity could provide potential targets to enhance ICB efficacy. Here, we showed that BAP1 inactivation fosters an immunosuppressive tumor microenvironment (TME), marked by increased infiltration of M2-like macrophages and neutrophils. Single-cell transcriptomic analysis revealed an expansion of SPP1+ neutrophils in ICB-treated, BAP1-inactivated tumors. These SPP1+ neutrophils displayed a pro-tumorigenic phenotype and conferred resistance to anti-PD-1 therapy by engaging with cytotoxic T cells via PD-1/PD-L1 signaling. Notably, depletion of neutrophils, but not macrophages, restored sensitivity to ICB in BAP1-inactivated tumors. Mechanistically, BAP1 loss significantly increased CCL2 secretion, driving neutrophil SPP1+ polarization, delaying neutrophil apoptosis, and promoting ICB resistance. This resistance could be significantly mitigated by targeting the CCL2-CCR2 axis. These results underscore the role of BAP1 in modulating the immune landscape and suggest that targeting CCL2-CCR2-mediated neutrophil polarization may overcome ICB resistance in BAP1-inactivated tumors.
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Project description:The deubiquitinase BAP1 is a candidate tumor suppressor regulating cell proliferation in human and is required for development in Drosophila. BAP1 is assembled into high molecular weight transcriptional multi-protein complexes. In order to identify potential BAP1 target genes, global mRNA expression profiling using microarrays was conducted. U2OS cells, transfected with a non-target control shRNA or shRNAs targeting BAP1, were selected with puromycin containing medium and then synchronized at the G1/S border to allow comparative analysis of gene expression.
2010-11-05 | E-GEOD-23035 | biostudies-arrayexpress
Project description:We report the genome wide binding sites of BAP1, HCF1 and OGT in bone marrow derived macrophages. De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor–1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans. For BAP1, bone marrow derived macrophages were used differentiated from bone marrow cells of BAP1-3X Flag Tagged KI mice we generated. For OGT and HCF1, bone marrow derived macrophages were used from BAP1 WT mice.
2012-11-07 | E-GEOD-40723 | biostudies-arrayexpress
Project description:RNA-seq of UPMM3 with restoration of BAP1 and BAP1 mutant proteins. Cell line UPMM3 contains a frameshift mutation in BAP1.
2018-01-31 | GSE97224 | GEO
Project description:Analysis of the effect that reduced BAP1 levels have on global gene expression.The hypothesis tested was that reduction in BAP1 levels would produce changes in gene expression similar to changes observed in class 2 uveal melanomas. Data provided insight into genes that are disrupted with reduced BAP1 levels. Total RNA was isolated from 92.1 cells transfected with either control or BAP1 knockdown constructs for global expression analysis.
2011-01-06 | E-GEOD-24896 | biostudies-arrayexpress
Project description:The BRCA1-associated protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase (UCH), which forms a multi-protein complex with different epigenetic factors such as ASXL1-3, and FOXK1/2. At chromatin, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex, and therefore functions as a transcriptional activator. However, the crosstalk between different subunits and how these subunits impact BAP1 function remains unclear. Here, we report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at chromatin. We further identified a previously uncharacterized Drosophila protein, the six-banded (SBA), as the ortholog of human MBD5/6. We demonstrated the core module of the BAP1 complex is structurally and functionally conserved during the evolution from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in each subunit is frequent in human cancer. In BAP1-dependent human cancers, MBD6 tends to be a dominant form. Depletion of MBD6 leads to a global loss of BAP1 occupancy at chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. In summary, our study has uncovered MBD5/6 as important regulators of the BAP1 complex and transcription, and sheds light on the therapeutic potential of targeting MBD5/6 in human cancer.
2022-09-15 | GSE196860 | GEO
Project description:BAP1 has been studied as a tumor suppressor. Our aim was to characterize genes that were altered in various hematopoietic cell types upon deletion of BAP1. BAP1 WT versus KO cells.
2012-11-07 | E-GEOD-40541 | biostudies-arrayexpress
Project description:Histone H3K4 methylation is a feature of meiotic recombination hotspots shared by many organisms including plants and mammals. Meiotic recombination is initiated by programmed double strand break (DSB) formation that in budding yeast is directed in gene promoters by histone H3K4 di/trimethylation. This histone modification is indeed recognized by Spp1, a PHD-finger containing protein that belongs to the conserved histone H3K4 methyltransferase Set1 complex. During meiosis, Spp1 binds H3K4me and recruits a DSB protein, Mer2, to promote DSB formation close to gene promoters. How Set1C and Mer2 related functions of Spp1 are connected is not clear.
2018-01-30 | PXD007590 | Pride
Project description:BRCA1-associated protein 1 (BAP1) is a multidomain deubiquitinase (DUB) with a ubiquitin carboxyl-terminal hydrolase (UCH) domain at its N-terminus. BAP1 mainly localizes in the nucleus and primarily functions as a transcriptional regulator in diverse cellular pathways, including cell proliferation, cell cycle progression, cell death and DNA repair. However, a comprehensive understanding of the mechanism by which the nucleocytoplasmic trafficking of BAP1 is regulated remains lacking. To identify protein factors that may be responsible for the nuclear import of BAP1, we used transiently expressed a N-terminally FLAG-tagged BAP1 in HEK293 freestyle (HEK293F) cells as a bait to pull down BAP1-interacting proteins for mass spectrometry-based proteomic analysis.
2022-04-14 | PXD030044 | Pride
Project description:BRCA-1 Associated Protein (BAP1) is a deubiquitinating enzyme that acts as a tumour suppressor. Inactivating mutations in the BAP1 gene have been identified in many cancers including cholangiocarcinoma, hepatocellular carcinoma, mesothelioma, uveal melanoma and renal cell carcinoma. Current standard therapeutic approaches for BAP1-deficient tumours are not particularly promising, contributing to poor overall survival and disease-free survival rates. Here, we found BAP1 to mediate the turnover of the key proteins in the DNA nucleotide excision repair (NER) pathway, and therefore promotes DNA repair. Importantly, we demonstrate that the loss of functional BAP1 sensitise tumour cells to LSD1 inhibitor, SP2509, in vitro and in vivo, through further impairment of NER efficiency. When used in combination with PARP1 inhibitor, Olaparib, we show that a synergistic drug combination response is achieved. Overall, our study identifies a drug combination approach that has the potential to be exploited clinically to target BAP1 deficient tumours.
2022-09-15 | PXD028470 | JPOST Repository