Mus musculus
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ABSTRACT:
PROVIDER: PRJNA381143 | ENA |
REPOSITORIES: ENA
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Project description:There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
2022-10-02 | GSE189771 | GEO
Project description:There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
2022-10-02 | GSE189769 | GEO
Project description:There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
2022-10-02 | GSE189767 | GEO
Project description:There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
2022-10-02 | GSE189772 | GEO
Project description:Transient activation of tumor-associated macrophages boosts anti-tumor immunity
| PRJNA389686 | ENA
Project description:Decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily and is up-regulated in tumors that originate from a diversity of lineages. DcR3 is capable of promoting angiogenesis, inducing dendritic cell apoptosis, and modulating macrophage differentiation. Since tumor-associated macrophages (TAMs) are the major infiltrating leukocytes in most malignant tumors, we used microarray technology to investigate whether DcR3 contributes to the development of TAMs. Among the DcR3-modulated genes expressed by TAMs, those that encode proteins involved in MHC class II (MHC-II)-dependent antigen presentation were down-regulated substantially, together with the master regulator of MHC-II expression (the class II transactivator, CIITA). The ERK- and JNK-induced deacetylation of histones associated with the CIITA promoters was responsible for DcR3-mediated down-regulation of MHC-II expression. Furthermore, the expression level of DcR3 in cancer cells correlated inversely with HLA-DR levels on TAMs and with the overall survival time of pancreatic cancer patients. The role of DcR3 in the development of TAMs was further confirmed using transgenic mice over-expressing DcR3. This elucidates the molecular mechanism of impaired MHC-II-mediated antigen presentation by TAMs, and raises the possibility that subversion of TAM-induced immunosuppression via inhibition of DcR3 expression might represent a target for the design of new therapeutics. Experiment Overall Design: Freshly isolated human monocytes were cultured with DcR3 or control hIgG1 in the presence of M-CSF for 2 days. Data were collected from two independent donors
2008-04-05 | E-GEOD-10856 | biostudies-arrayexpress
Project description:Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood if and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we found that peptidylarginine deiminase 4 (PAD4) manifested the highest expression among common PTM enzymes in TAMs and negatively correlated to clinical response to immune checkpoint blockade (ICB). Genetic and pharmacological inhibition of PAD4 in macrophages prevented tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage MHC-II expression and T-cell effector function. Mechanistically, PAD4 citrullinated STAT1 at arginine 121 (R121), thereby promoting the interaction between STAT1 and PIAS1; and the loss of PAD4 abolished this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC-II machinery in macrophages and enhancing T-cell activation. Thus, the PAD4-STAT1-PIAS1 axis is a previously unknown intrinsic immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.
2024-05-22 | PXD049188 | Pride
Project description:The major histocompatibility complex class II (MHC II) is important for the adaptive immune response because it presents processed antigens to CD4-positive T-cells. Conventional chemotherapeutic agents (e.g., melphalan, adriamycin, hydroxyurea) induce tumor cell death by causing DNA double strand breaks (DSBs), which are crucial for anti-tumor effects. However, the cellular response induced at low doses of these agents that do not cause immediate cell death is unclear. We have employed microarray expression profiling to identify genes which are induced by low dose of chemotherapeutic agents. Multiple myeloma cell line KMS12PE was treated with vehicle, 2 μM melphalan, or 50 nM adriamycin. These agents transcriptionally induced the major histocompatibility complex class II (MHC II) genes. They also increased the expressions of MHC class II transactivator (CIITA), the master regulator of MHC II genes and interferon regulatory factor 1 (IRF1), a transcription factor for CIITA.
2021-03-19 | GSE151040 | GEO
Project description:There is a growing recognition of the prognostic significance associated with the expression of major histocompatibility complex (MHC) class II in tumor cells within the context of anti-cancer immunity. Mutations or homozygous deletions of MHC-II genes are frequently encountered in B-cell lymphomas that develop in immune-privileged sites, and therefore have been linked to the survival of patients with B-cell lymphoma. However, the understanding of the regulation of MHC class II expression by epigenetic and genetic factors remains incomplete. In this study, we have identified a crucial signaling pathway comprised of the histone H2AK119 deubiquitinase BAP1, the interferon regulatory factor IRF1, and the MHC-II transactivator CIITA, which directly activates the expression of MHC-II cluster genes. Disruption of the BAP1/IRF1/CIITA axis leads to a functional attenuation of MHC-II expression without affecting expression of the genes involved in cell cycle or proliferation. Notably, loss of BAP1 has no effect on B cell lymphoma cell growth in vitro while significantly accelerates tumor growth in immunocompetent mice in vivo. Indeed, by utilizing single-cell RNA-seq, a significant reduction in immune cell infiltration was observed in BAP1-depleted tumors, indicating a potential tumor suppressive function of BAP1 by regulating the tumor microenvironment and immune response. Finally, we demonstrated that pharmacological inhibition of PRC1, which deposits histone H2K119Ub and functions as an antagonist of BAP1, could rescue the MHC-II genes in BAP1 deficient B-cell lymphoma cells. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression and enhancing immunotherapy outcomes at epigenetic levels in B-cell lymphoma treatment.
2024-12-20 | GSE276031 | GEO
Project description:To understand how the combination of ORIN1001 plus docetaxel promotes anti-tumor immunity, we performed single-cell RNA sequencing (scRNA-seq) of CD45+ cells from 2153L tumors. Our data found that combo induces CD8+ T cells that express high levels of T cell activation, cytotoxicity, and exhaustion genes. combo also increase the cDC1 and MHC-II high macrophages which exhibited higher M1-like macrophages scores.
2024-10-16 | GSE276356 | GEO