PI3Kg in B cells promotes antibody responses and generation of antibody-secreting cells [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE269303 | GEO | 2024/06/26
REPOSITORIES: GEO
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Project description:The differentiation of naïve and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B-lineage cells have not. Here we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses using mouse models with bulk and single-cell transcriptome as well as B cell receptor repertoire sequencing.
2024-06-26 | GSE269300 | GEO
Project description:Trained immunity and immune tolerance have been identified as long-term response patterns of the innate immune system. The causes of these opposing reactions remain elusive. Here we report about differential inflammatory responses of microglial cells derived from neonatal mouse brain to increasing doses of the endotoxin LPS. Prolonged priming with ultra-low LPS doses provokes trained immunity, i.e. increased production of pro-inflammatory mediators in comparison to the unprimed control. In contrast, priming with high doses of LPS induces immune tolerance implying decreased production of inflammatory mediators and pronounced release of anti-inflammatory cytokines. Investigation of the signaling processes and cell functions involved in these memory-like immune responses reveals essential role of phosphoinositide 3-kinase γ (PI3Kγ), one of the phosphoinositide 3-kinase species highly expressed in innate immune cells. Together, our data suggest profound influence of preceding contacts with pathogens on the immune response of microglia. The impact of these interactions – trained immunity or immune tolerance - appears to be shaped by pathogen dose.
2019-12-05 | GSE137741 | GEO
Project description:The isoform delta of class I Phosphoinositide 3-kinase (PI3Kδ) is expressed primarily in hematopoietic cells, and its inhibitor, idelalisib, is approved for the treatment of leukemia and lymphoma. PI3K orients the apicobasal axis and regulates lumen formation through assembly of the extracellular matrix. PI3Kδ overexpression in hepatocellular carcinoma (HCC) cells (Huh7) leads to profound changes in cell morphogenesis and is associated to the up-regulation of stem cell markers. Transcriptomic analysis performed in triplicate on mRNA of Huh7 cells transfected with PI3Kδ construct (PI3KCD) revealed down regulation of transcripts of hepatocyte differentiation genes and up regulation of transcripts that allow prediction of ICC and mesenchymal stem cells.
2020-11-30 | GSE128022 | GEO
Project description:Phosphoinositide 3-kinases (PI3Ks) play a central role in adaptive immunity by transducing signals from the T cell antigen receptor (TCR) via production of PIP3. PI3Kδ is a heterodimer composed of a p110δ catalytic subunit associated with a p85α or p85β regulatory subunit and is preferentially engaged by the TCR upon T cell activation. The molecular mechanisms leading to PI3Kδ recruitment and activation at the TCR signalosome remain unclear. In this study, we have used affinity purification coupled with quantitative mass spectrometry to uncover the p110δ interactome in primary CD4+ T cells. Moreover, we have determined how the PI3Kδ interactome changes upon the differentiation of small naïve T cells into T cell blasts expanded in the presence of IL-2.
2021-03-08 | PXD022607 | Pride
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 kinase as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-19 | PXD045702 | Pride
Project description:Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.
2022-03-02 | GSE166148 | GEO
Project description:Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.
2022-03-02 | GSE166149 | GEO
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-18 | GSE243669 | GEO
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-18 | GSE243666 | GEO
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-18 | GSE243654 | GEO