Targeting an alternate Wilms Tumor Antigen-1 peptide bypasses immunoproteasome dependency
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190501 | GEO | 2022/09/30
REPOSITORIES: GEO
Similar Datasets
Project description:Designing effective antileukemic immunotherapy will require understanding mechanisms underlying tumor control or resistance. Here, we report a mechanism of escape from immunologic targeting in an acute myeloid leukemia (AML) patient, who relapsed 1 year after immunotherapy with engineered T cells expressing a human leukocyte antigen A*02 (HLA-A2)-restricted T cell receptor (TCR) specific for a Wilms' tumor antigen 1 epitope, WT1126-134 (TTCR-C4). Resistance occurred despite persistence of functional therapeutic T cells and continuous expression of WT1 and HLA-A2 by the patient's AML cells. Analysis of the recurrent AML revealed expression of the standard proteasome, but limited expression of the immunoproteasome, specifically the beta subunit 1i (β1i), which is required for presentation of WT1126-134. An analysis of a second patient treated with TTCR-C4 demonstrated specific loss of AML cells coexpressing β1i and WT1. To determine whether the WT1 protein continued to be processed and presented in the absence of immunoproteasome processing, we identified and tested a TCR targeting an alternative, HLA-A2-restricted WT137-45 epitope that was generated by immunoproteasome-deficient cells, including WT1-expressing solid tumor lines. T cells expressing this TCR (TTCR37-45) killed the first patients' relapsed AML resistant to WT1126-134 targeting, as well as other primary AML, in vitro. TTCR37-45 controlled solid tumor lines lacking immunoproteasome subunits both in vitro and in an NSG mouse model. As proteasome composition can vary in AML, defining and preferentially targeting these proteasome-independent epitopes may maximize therapeutic efficacy and potentially circumvent AML immune evasion by proteasome-related immunoediting.
| S-EPMC8985599 | biostudies-literature
Project description:Targeting an alternate Wilms Tumor Antigen-1 peptide bypasses immunoproteasome dependency
| PRJNA787299 | ENA
Project description:The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes known to be involved in shaping adaptive immune responses, but their role for innate immune signaling is elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages which are highly specialized tissue macrophages of the alveolar surface of the lung. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNγ transcriptionally induced all three immunoproteasome subunits LMP2, LMP7, and MECL-1. In contrast, IL-4 triggered alternative (M2) activation was accompanied by posttranscriptional upregulation of LMP2 and LMP7. Accordingly, immunoproteasome activity increased in M1 cells, and to some extent under M2 conditions. Analyzing the polarization capability from LMP7 deficient mice revealed no effect on the LPS/IFNγ triggered M1 profile, but uncovered a distorted M2 profile for IL-4 stimulated LMP7-/- alveolar macrophages as characterized by increased M2 marker gene expression and CCL17 cytokine release. This shift in immunoproteasome-dependent M2 polarization was accompanied by amplified AKT/STAT6 activation and IRF4 expression in LMP7-/- alveolar macrophages. IL-13 stimulation of LMP7 deficient cells induced a similar M2 skewed profile and IL4Rα protein expression was generally elevated in LMP7-/- alveolar macrophages, indicating that amplified IL4R signaling in immunoproteasome defective cells may contribute to augmented M2 polarization. Importantly, treatment with an LMP7-specific proteasome inhibitor recapitulated the findings of genetic LMP7 inactivation. Our results thus suggest a novel role of immunoproteasome function for regulating innate immune function of macrophages by limiting IL4R expression and signaling. Expression data of M0 and M2 macrophages derived from Lmp7 k.o. and control animals
2016-06-29 | E-GEOD-72000 | biostudies-arrayexpress
Project description:Proteasomes hydrolyze most intracellular proteins. Immunoproteasome is a specific form of proteasome implicated in inflammation, cancer and autoimmune diseases. Modulation of immunoproteasome activity and content is a promising direction for the management of socially important pathologies. Using previously obtained reporter colorectal cancer cell lines, we tested how various commonly used compounds including ibuprofen, acetylsalicylic acid, vitamin C, caffeine and others, affect immunoproteasome expression. Methods: Immunoproteasome subunit expression was assessed by flow cytometry, qPCR and Western blot. Proteasome activity was tested using fluorogenic substrates and the activity probe. Transcriptome analysis was performed to identify patterns of gene expression changes. Results: Among the tested compounds caffeine was the only drug that revealed modest reduction in quantity of immunoproteasomes. The effect of caffeine on immunoproteasomes varied between cell lines and was stronger as a result of prolonged treatment. The reduction of immunoproteasome content in cells treated with caffeine coincided with decreased expression of immunoproteasome subunits and downregulation of Nrf3 transcription factor and a PAC4 proteasome assembly chaperone. Moreover, decreased expression of immunoproteasome subunits in cells treated with caffeine coincided with the reduction of oxidative stress levels. Caffeine did not affect the degradation of immunoproteasomes by autophagy. Conclusions: Modulation of immunoproteasome expression by caffeine might help to optimize existing and develop novel strategies for the treatment of colorectal cancer and several autoimmune diseases.
2024-10-22 | GSE279800 | GEO
Project description:The proteasome is a central regulatory hub for intracellular signaling by degrading numerous signaling mediators. Immunoproteasomes are specialized types of proteasomes known to be involved in shaping adaptive immune responses, but their role for innate immune signaling is elusive. Here, we analyzed immunoproteasome function for polarization of alveolar macrophages which are highly specialized tissue macrophages of the alveolar surface of the lung. Classical activation (M1 polarization) of primary alveolar macrophages by LPS/IFNγ transcriptionally induced all three immunoproteasome subunits LMP2, LMP7, and MECL-1. In contrast, IL-4 triggered alternative (M2) activation was accompanied by posttranscriptional upregulation of LMP2 and LMP7. Accordingly, immunoproteasome activity increased in M1 cells, and to some extent under M2 conditions. Analyzing the polarization capability from LMP7 deficient mice revealed no effect on the LPS/IFNγ triggered M1 profile, but uncovered a distorted M2 profile for IL-4 stimulated LMP7-/- alveolar macrophages as characterized by increased M2 marker gene expression and CCL17 cytokine release. This shift in immunoproteasome-dependent M2 polarization was accompanied by amplified AKT/STAT6 activation and IRF4 expression in LMP7-/- alveolar macrophages. IL-13 stimulation of LMP7 deficient cells induced a similar M2 skewed profile and IL4Rα protein expression was generally elevated in LMP7-/- alveolar macrophages, indicating that amplified IL4R signaling in immunoproteasome defective cells may contribute to augmented M2 polarization. Importantly, treatment with an LMP7-specific proteasome inhibitor recapitulated the findings of genetic LMP7 inactivation. Our results thus suggest a novel role of immunoproteasome function for regulating innate immune function of macrophages by limiting IL4R expression and signaling.
2016-06-29 | GSE72000 | GEO
Project description:One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine thatpotetiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I) that significantly promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex,as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigenprocessing activity of immunoproteasome, leading to enhanced major histocompatibility class I(MHC-I)-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation, empowers T-cell cytotoxicity, and thus elevates the tumorresponse to immunotherapy.
2021-03-31 | GSE171158 | GEO
Project description:Cerebral malaria (CM) lethality is attributable to brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored. Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in cerebral malaria (CM) development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to Plasmodium berghei-infected erythrocytes (PbA-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing, and folding and antigen presentation. In vitro assays show that Type 1 IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/ß-catenin signaling pathway. We demonstrate that IE exposure induces a substantial increase in BECs glucose uptake while glycolysis blockade abrogates INFb secretion impairing immunoproteasome activation, antigen presentation, and Wnt/ ß-catenin signaling. Metabolome analysis show that energy demand and production are markedly increased in BECs exposed to IE as revealed by enriched content in glucose and fatty acid catabolites. In accordance, glycolysis blockade in vivo delayed the clinical onset of CM in mice. Our results unveiled that Type 1 IFN signaling and subsequent immunoproteasome activation in BECs contribute to enhanced antigen presentation and the impairment of the endothelial barrier function. We also show that Type 1 IFN signaling and its downstream effects are licensed by dramatic increase in glucose uptake with an impact on energy metabolism pathways. This work raises the hypothesis that Type 1 IFN- immunoproteasome induction response in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells, which is a determinant of brain cytotoxic edema and (2) by promoting endothelial barrier dysfunction, that likely favors brain vasogenic edema.
2023-03-13 | PXD039805 | Pride
Project description:Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.
2024-05-31 | GSE266962 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.
2024-05-31 | GSE266865 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.
2024-05-31 | GSE266864 | GEO