Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA381143 | ENA |
REPOSITORIES: ENA
Similar Datasets
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 | GSE189772 | 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.
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Project description:Despite the importance of tumor-associated macrophages (TAMs) in modulating anti-tumor immunity, the molecular determinants of their functional phenotypes remain elusive. Through a large-scale CRISPR screen, we discovered that tumor-derived lactic acid, PGE2, and GM-CSF collaboratively shape the highly conserved but mutually exclusive TAM phenotypes: MHC-II+ and angiogenic TAMs. Mechanistically, the dichotomous nature of these two phenotypes is driven by the antagonistic interactions between lactic acid/PGE2 and GM-CSF. Lactic acid and PGE2 coordinately induce the angiogenic gene program while suppressing the GM-CSF-induced MHC-II program at chromatin level. This mechanism leads to distinct spatial distribution of TAMs, with angiogenic TAMs in lactate-rich hypoxic regions and MHC-II+ TAMs outside these areas. Furthermore, in vivo genetic perturbation of TAMs showed that shifting TAMs to an interferon responsive program, triggered by Adar inactivation, substantially potentiates anti-tumor immunity. Our findings suggest a conserved mechanism of TAM polarization and a potential approach for reprogramming TAMs in immunotherapy.
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Project description:Despite the importance of tumor-associated macrophages (TAMs) in modulating anti-tumor immunity, the molecular determinants of their functional phenotypes remain elusive. Through a large-scale CRISPR screen, we discovered that tumor-derived lactic acid, PGE2, and GM-CSF collaboratively shape the highly conserved but mutually exclusive TAM phenotypes: MHC-II+ and angiogenic TAMs. Mechanistically, the dichotomous nature of these two phenotypes is driven by the antagonistic interactions between lactic acid/PGE2 and GM-CSF. Lactic acid and PGE2 coordinately induce the angiogenic gene program while suppressing the GM-CSF-induced MHC-II program at chromatin level. This mechanism leads to distinct spatial distribution of TAMs, with angiogenic TAMs in lactate-rich hypoxic regions and MHC-II+ TAMs outside these areas. Furthermore, in vivo genetic perturbation of TAMs showed that shifting TAMs to an interferon responsive program, triggered by Adar inactivation, substantially potentiates anti-tumor immunity. Our findings suggest a conserved mechanism of TAM polarization and a potential approach for reprogramming TAMs in immunotherapy.
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Project description:Despite the importance of tumor-associated macrophages (TAMs) in modulating anti-tumor immunity, the molecular determinants of their functional phenotypes remain elusive. Through a large-scale CRISPR screen, we discovered that tumor-derived lactic acid, PGE2, and GM-CSF collaboratively shape the highly conserved but mutually exclusive TAM phenotypes: MHC-II+ and angiogenic TAMs. Mechanistically, the dichotomous nature of these two phenotypes is driven by the antagonistic interactions between lactic acid/PGE2 and GM-CSF. Lactic acid and PGE2 coordinately induce the angiogenic gene program while suppressing the GM-CSF-induced MHC-II program at chromatin level. This mechanism leads to distinct spatial distribution of TAMs, with angiogenic TAMs in lactate-rich hypoxic regions and MHC-II+ TAMs outside these areas. Furthermore, in vivo genetic perturbation of TAMs showed that shifting TAMs to an interferon responsive program, triggered by Adar inactivation, substantially potentiates anti-tumor immunity. Our findings suggest a conserved mechanism of TAM polarization and a potential approach for reprogramming TAMs in immunotherapy.
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Project description:Despite the importance of tumor-associated macrophages (TAMs) in modulating anti-tumor immunity, the molecular determinants of their functional phenotypes remain elusive. Through a large-scale CRISPR screen, we discovered that tumor-derived lactic acid, PGE2, and GM-CSF collaboratively shape the highly conserved but mutually exclusive TAM phenotypes: MHC-II+ and angiogenic TAMs. Mechanistically, the dichotomous nature of these two phenotypes is driven by the antagonistic interactions between lactic acid/PGE2 and GM-CSF. Lactic acid and PGE2 coordinately induce the angiogenic gene program while suppressing the GM-CSF-induced MHC-II program at chromatin level. This mechanism leads to distinct spatial distribution of TAMs, with angiogenic TAMs in lactate-rich hypoxic regions and MHC-II+ TAMs outside these areas. Furthermore, in vivo genetic perturbation of TAMs showed that shifting TAMs to an interferon responsive program, triggered by Adar inactivation, substantially potentiates anti-tumor immunity. Our findings suggest a conserved mechanism of TAM polarization and a potential approach for reprogramming TAMs in immunotherapy.
2025-08-03 | GSE269028 | GEO
Project description:Despite the importance of tumor-associated macrophages (TAMs) in modulating anti-tumor immunity, the molecular determinants of their functional phenotypes remain elusive. Through a large-scale CRISPR screen, we discovered that tumor-derived lactic acid, PGE2, and GM-CSF collaboratively shape the highly conserved but mutually exclusive TAM phenotypes: MHC-II+ and angiogenic TAMs. Mechanistically, the dichotomous nature of these two phenotypes is driven by the antagonistic interactions between lactic acid/PGE2 and GM-CSF. Lactic acid and PGE2 coordinately induce the angiogenic gene program while suppressing the GM-CSF-induced MHC-II program at chromatin level. This mechanism leads to distinct spatial distribution of TAMs, with angiogenic TAMs in lactate-rich hypoxic regions and MHC-II+ TAMs outside these areas. Furthermore, in vivo genetic perturbation of TAMs showed that shifting TAMs to an interferon responsive program, triggered by Adar inactivation, substantially potentiates anti-tumor immunity. Our findings suggest a conserved mechanism of TAM polarization and a potential approach for reprogramming TAMs in immunotherapy.
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