A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing
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ABSTRACT:
PROVIDER: PRJNA544340 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9110550_1.fastq.gz | Fastqsanger.gz | |||
| SRR9110550_2.fastq.gz | Fastqsanger.gz | |||
| SRR9110560_1.fastq.gz | Fastqsanger.gz | |||
| SRR9110560_2.fastq.gz | Fastqsanger.gz | |||
| SRR9110551_1.fastq.gz | Fastqsanger.gz |
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Project description:A Major Chromatin Regulator Determines Resistance of Tumor Cells to T cell Mediated Killing
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Project description:Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-gamma, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.
2018-01-08 | GSE107670 | GEO
Project description:Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes—including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex—sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.
2019-05-22 | GSE131674 | GEO
Project description:Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes-including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex-sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-?, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.
| S-EPMC5953516 | biostudies-literature
Project description:Mycobacterium smegmatis is a model non-pathogenic mycobacterium that is efficiently killed by macrophages. Here, we explore the role of NF-?B in the innate immune response, focusing in detail on the mechanisms of the first killing period (1-4h) of M. smegmatis which coincides with phagosome-lysosome fusion. We show that infection of macrophages with M. smegmatis induces an activation of NF-?B and this activation is required for killing since treatment of macrophages with NF-?B inhibitors or siRNA silencing of the NF-?B subunit p65 increases bacterial survival. NF-?B induced proteins were thus hypothesized to be essential during the first phase of M. smegmatis killing. We therefore identified, using RNA microarray, the genes that were regulated during infection in the absence and presence of NF-?B inhibitors. By subtraction this provided a list of pro-inflammatory proteins that were under the control of NF-?B and putatively involved in the killing response. Among these category of genes were those for lysosomal enzymes and membrane trafficking regulators, including Cathepsins, LAMP-2 and Rab34, are regulated by NF-?B. Moreover, inhibition of NF-?B signaling retarded the delivery of v-ATPase, LAMP-2, CtsZ and CtsH thereby impairing the maturation of mycobacterial phagosomes. Collectively; our data provide the first compelling evidence that the innate immune response via NF-?B activation is linked to phagosome fusion with lysosomes that is essential for killing of mycobacteria. Keywords: NFkB inhibitor treated vs untreated The study includes J774 macrophage cell lines which are infected with Mycobacterium smegmatis in the presence and absense of NFkB inhibitor SC-514.Total RNA was isolated from individual samples and each sample was hybridised to CodeLink Mouse whole genome bioarray slides.This study was intended to know the role of NFkB regulated genes in killing non-pathogenic mycobacteria during 4 hour post infection of macrophages.
2007-10-23 | E-GEOD-8999 | biostudies-arrayexpress
Project description:For over 130 years, invasive pneumococcal disease has been associated with the presence of extracellular diplococci or short chains in affected tissues. Herein, we show that Streptococcus pneumoniae that invade the myocardium from the bloodstream replicate within cellular vesicles and transition into non-purulent biofilms. Pneumococci within cardiac microlesions exhibited salient biofilm properties including intrinsic resistance to antibiotic killing and the presence of an extracellular matrix. Dual RNA-seq data generated from heart- and blood-isolated pneumococci confirmed the biofilm phenotype in vivo and revealed stark anatomical site-specific differences in virulence gene expression; the latter having major implications on vaccine antigen selection. Genes within three genomic islands were identified as exclusively expressed in vivo. Deletion of one such island, i.e. Region of Diversity 12, resulted in a biofilm-deficient and highly inflammogenic phenotype, suggesting a link between the ability to form biofilms and a dampened host-response. We subsequently determined that biofilm pneumococci subvert cytokine/chemokine production and myocardial neutrophil infiltration by rapidly killing cardiac macrophages in a pneumolysin dependent manner. Our findings contradict the emerging notion that biofilm pneumococci are immunoquiescent and instead show that biofilm S. pneumoniae actively suppress the host response through pneumolysin-mediated immune cell killing.
2017-08-21 | GSE86118 | GEO
Project description:Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain. We asked what abnormality impairs elimination when a bacterium lands on the pristine surface of a newborn CF airway? To investigate this defect, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO3- transport. Without CFTR, airway epithelial HCO3- secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying ASL pH or bacterial killing could report on the benefit of therapeutic interventions. 11 samples of trachea primary airway epithelial cultures representing CFTR+/+ and CFTR-/- pigs. Pig samples representing 14 bronchus and 12 trachea tissue samples submitted in GSE21071.
2012-03-29 | E-GEOD-36906 | biostudies-arrayexpress
Project description:Mycobacterium smegmatis is a model non-pathogenic mycobacterium that is efficiently killed by macrophages. Here, we explore the role of NF-κB in the innate immune response, focusing in detail on the mechanisms of the first killing period (1-4h) of M. smegmatis which coincides with phagosome-lysosome fusion. We show that infection of macrophages with M. smegmatis induces an activation of NF-κB and this activation is required for killing since treatment of macrophages with NF-κB inhibitors or siRNA silencing of the NF-κB subunit p65 increases bacterial survival. NF-κB induced proteins were thus hypothesized to be essential during the first phase of M. smegmatis killing. We therefore identified, using RNA microarray, the genes that were regulated during infection in the absence and presence of NF-κB inhibitors. By subtraction this provided a list of pro-inflammatory proteins that were under the control of NF-κB and putatively involved in the killing response. Among these category of genes were those for lysosomal enzymes and membrane trafficking regulators, including Cathepsins, LAMP-2 and Rab34, are regulated by NF-κB. Moreover, inhibition of NF-κB signaling retarded the delivery of v-ATPase, LAMP-2, CtsZ and CtsH thereby impairing the maturation of mycobacterial phagosomes. Collectively; our data provide the first compelling evidence that the innate immune response via NF-κB activation is linked to phagosome fusion with lysosomes that is essential for killing of mycobacteria. Keywords: NFkB inhibitor treated vs untreated
2007-10-23 | GSE8999 | GEO
Project description:Penetration of immune cells into tumor cells was believed to be immune-suppressive via cell-in-cell (CIC) mediated death of the internalized immune cells. We unexpectedly found that CIC formation largely led to the death of the host tumor cells, but not the internalized immune cells, manifesting typical features of death executed by NK cells, which we called “in-cell killing” that demonstrates efficacy superior to the canonical way of “kiss killing” from outside. By expression profiling of isogenic cells, CD44 on tumor cells was identified as a negative regulator of “in-cell killing” via inhibiting CIC formation. CD44 functions to antagonize NK cell internalization by reducing N-cadherin-mediated intercellular adhesion and enhancing Rho GTPase-regulated cellular stiffness as well. Remarkably, antibody-mediated blockade of CD44 signaling potentiated the suppressive effects of NK cells on tumor growth associated with increased heterotypic CIC formation. Together, we identified CIC-mediated “in-cell killing” as a promising strategy for cancer immunotherapy.
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