PTIR1 acts as a suppressor of immunoproteasome and promotes cancer immune resistance
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ABSTRACT:
PROVIDER: PRJNA714384 | ENA |
REPOSITORIES: ENA
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Project description:Cancer cells evade host immune surveillance by virtue of poor immunogenicity. We identify a novel oncogene that acts as a promotor of tumor immune resistance, designated as PTIR1. Tumor-intrinsic PTIR1 is induced by RNA splicing and highly correlated with poor outcome of patients with cancer.
2024-02-19 | GSE168862 | GEO
Project description:PTENα functions as an immune suppressor and promotes immune resistance in PTEN-mutant cancer
| PRJNA704696 | 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:Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+ T cells
| PRJNA989185 | ENA
Project description:scRNAseq reveals immune evasion from engineered T cell receptor gene therapy by acquisition of immunoproteasome deficiency in acute myeloid leukemia
2022-09-30 | GSE190501 | GEO
Project description:As a tumor suppressor, PTEN is frequently mutated in human cancers and PTEN mutants promote tumor progression and metastasis. PTEN mutations have been implicated in immune regulation, but the underlying mechanism is largely unknown. We report that PTENα, the isoform of PTEN, remains active in cancer bearing stop-gained PTEN mutations. Through counteraction of CD8+ T cell-mediated cytotoxicity, presence of PTENα leads to T cell dysfunction and accelerates immune-resistant cancer progression. Clinical analysis further uncovers that PTENα-active mutations suppress host immune responses and result in poor prognosis in cancer as relative to PTENα-inactive mutations. Furthermore, germline deletion of Ptenα in mice increases cell susceptibility to immune attack through augmenting stress granule formation and limiting synthesis of peroxidases, leading to massive oxidative cell death and severe inflammatory damage. We propose that PTENα protects tumor from T cell killing and thus PTENα is a potential target in antitumor immunotherapy.
2024-02-19 | GSE167469 | GEO
Project description:Hyperinsulinemia, often associated with obesity and type 2 diabetes mellitus, is also linked to an elevated risk of various cancers. However, the specific mechanisms underlying this connection remain unclear. Here, we report that inhibiting neddylation, in the presence of insulin treatment, further promotes cancer cell migration in different cancer types by activating both insulin receptor substrate 1 and 2, as well as the PI3K/AKT signaling pathway. We also found that C-CBL neddylates IRS1 and IRS2 as an E3 ligase, with clinical evidence supporting its role as a tumor suppressor. Altogether, these findings suggest that the neddylation of IRS1 and IRS2 may be a bona fide suppressor of cancer cell migration. Thus, caution is advised when considering neddylation inhibitors as a treatment for cancer patients with obesity-related type 2 diabetes or hyperinsulinemic condition.
2024-05-22 | PXD044760 | Pride
Project description:Tumors use various strategies for immune evasion. Understanding the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as an essential immune suppressor. We show that FGF21 is upregulated in multiple types of tumors and promotes tumor progression. FGF21 significantly disrupts CD8+T anti-tumor immune response by rewiring cholesterol metabolism of CD8+ T cells. We further reveal that FGF21 activates AKT-mTORC1- sterolregulatoryelementbindingprotein 1 (SREBP1) signal axis to enhance cholesterol biosynthesis in CD8+T cells. FGF21 knockdown or blockade of FGF21 by a neutralizing antibody attenuates AKT-mTORC1 signaling and subsequently decreases cholesterol content in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings uncover FGF21 as a “secreted immune checkpoint” to restrict anti-tumor immunity and suggest its inhibition is a useful strategy for improving the efficacy of cancer immunotherapy.
2024-06-29 | GSE236180 | GEO