In vivo CRISPR screens identify Mga as an immunotherapy target in triple-negative breast cancer
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ABSTRACT:
PROVIDER: PRJNA1050296 | ENA |
REPOSITORIES: ENA
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Project description:Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. We also provided a high-confidence valuable dataset for the understanding of tumor intrinsic immunomodulators and the discovery of novel anti-cancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances anti-tumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga functions through, at least partially, repression of MHC-II genes and related immune responses. Consistently, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-g signaling. Our findings provide new insights into tumor immune escape and pave the way for further exploration of MGA inhibition for clinical benefits in triple-negative breast cancer.
2024-09-06 | GSE249759 | GEO
Project description:Immune evasion is critical for tumor initiation and progression, as well as determining the efficacy of immunotherapies. Through iterative in vivo CRISPR screens within seven syngeneic tumor models, we not only identified the core immune evasion pathways and context-dependent ones across cancer types but also provided a high-confidence valuable dataset for understanding tumor intrinsic immunomodulators and discovering novel anti-cancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances anti-tumor immunity and inhibits the tumor growth of TNBC model. Transcriptomics and single cell-RNA (sc-RNA) seq analyses revealed Mga function through, at least partially, repression of MHC-II genes and related immune responses. Consistently, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-g signaling. Our findings provide new insights into tumor immune escape and pave the way for further exploration of MGA inhibition for clinical benefits in triple-negative breast cancer.
2024-09-06 | GSE249758 | GEO
Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
2006-08-31 | GSE4598 | GEO
Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
2006-08-31 | GSE4597 | GEO
Project description:The transcriptional regulator Mga of Streptococcus pyogenes (the group A streptococcus, GAS) is known to directly activate several virulence genes important for colonization and immune evasion during exponential growth. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to the uptake and metabolism of sugars. Although the divergent M1 and M4 Mga profiles were similar in size and content, the M6 JRS4 strain was clearly distinct, even from other M6 strains. Real-time RT-PCR and northern blot analysis validated our microarray results and confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. A novel ORF (Spy2036) encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga or grm. Mga was shown to bind directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and is able to activate two divergently transcribed genes from a single site in a class II background. Both class and serotype specific Mga-regulated genes, such as speB, were apparent. In fact, Mga activated speB as long as it was expressed in the wild type strain, although direct binding of Mga to the PspeB promoter could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS. Keywords: Wild-type vs Mga-
2006-08-31 | GSE4596 | GEO
Project description:NF-kB associated markers of PD-1 immunotherapy response in early and metastatic triple negative breast cancer
2024-10-30 | GSE279896 | GEO
Project description:Immune checkpoint inhibitors exhibit limited response rates in patients with triple-negative breast cancer (TNBC), suggesting that additional immune escape mechanisms may exist. Here, we performed two-step customized in vivo CRISPR screens targeting disease-related immune genes using different mouse models with multidimensional immune-deficiency characteristics. In vivo screens characterized gene functions in the different tumor microenvironments and recovered canonical immunotherapy targets such as Ido1. In addition, functional screening and transcriptomic analysis identified Lgals2 as a candidate regulator in TNBC involving immune escape. Mechanistic studies demonstrated that tumor cell-intrinsic Lgals2 induced the increased number of tumor-associated macrophages, as well as the M2-like polarization and proliferation of macrophages through the CSF1/CSF1R axis, which resulted in the immunosuppressive nature of the TNBC microenvironment. Blockade of LGALS2 using an inhibitory antibody successfully arrested tumor growth and reversed the immune suppression. Collectively, our results provide a theoretical basis for LGALS2 as a potential immunotherapy target in TNBC.
| S-EPMC9242595 | biostudies-literature
Project description:Mutagenesis sensitizes murine models of triple negative breast cancer to immunotherapy
| PRJNA561596 | ENA
Project description:We sought understand the molecular mehcanism of gene regulation by Mga and its contribution to GAS pathogenesis in serotype M59 GAS through whole transcriptome analysis of strains with phosphorylation mimicking substitutions in key histidine residues of Mga. There were 6 strains analyzed, each in triplicate replicates: 1)wild-type GAS, 2)mga deletion strain 3)mga with alanine at H207 4)mga with aspartate at H207, 5) mga with alanine at H273 6)mga with aspartate at H273
2015-04-18 | E-GEOD-67988 | biostudies-arrayexpress