Targeted demethylation and activation of NLRC5 augments cancer immunogenicity through MHC class I
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ABSTRACT:
PROVIDER: PRJNA975212 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24694100_1.fastq.gz | Fastqsanger.gz | |||
| SRR24694100_2.fastq.gz | Fastqsanger.gz | |||
| SRR24694085_1.fastq.gz | Fastqsanger.gz | |||
| SRR24694085_2.fastq.gz | Fastqsanger.gz | |||
| SRR24694086_1.fastq.gz | Fastqsanger.gz |
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Project description:Impaired expression of MHC class I constitutes a major mechanism of immune evasion of cancers, leading to poor prognosis and resistance to checkpoint blockade therapies. Existing drugs for MHC class I have limited applicability due to severe side effects. Here we show a novel approach of robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA), NLRC5, using a CRISPR/Cas9 based gene-specific targeted demethylaion (TDM) system and targeted demethylation and activation (TDMa) system. The TDMa system specifically recruits a demethylating enzyme and transcriptional activators, providing efficient demethylation and transactivation of the NLRC5 promoter. TDMa in mouse and human cancer cells induced MHC class I antigen presentation and accelerated CD8+ T cell activation with tumor suppression effects both in vitro and in vivo. Moreover, enhanced immunogenicity by NLRC5 TDMa boosted efficacy of anti-PD1 therapy. Therefore, NLRC5 targeting by the TDMa system confers an attractive therapeutic approach against cancer.
2024-02-22 | GSE233194 | GEO
Project description:MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) factor CIITA, which is recruited to SXY regulatory modules of MHC promoters via a DNA-binding “enhanceosome” complex. NLRC5, another NLR protein, was recently found to control transcription of MHC class I (MHCI) genes. However, detailed understanding of its target-gene specificity and mechanism of action remained lacking. We therefore performed ChIP-sequencing experiments to gain comprehensive information on NLRC5-transactivated genes. In addition to classical MHCI genes, we identified novel NLRC5-targets exclusively in the H2-Q and H2-T regions of the MHCI locus, among which the best targets were found. Investigation of cells lacking the MHCII-enhanceosome factor RFX5 demonstrated its strict requirement for NLRC5 recruitment to the SXY module conserved in MHCI genes. Furthermore, patient-derived B cell lines deficient in RFX5, RFXAP, and RFXANK corroborated importance of the enhanceosome for MHCI transactivation. Although sharing similar SXY modules and common DNA-binding factors, CIITA and NLRC5 regulate distinct genes, as shown here using double-deficient Nlrc5-/-CIIta-/- mice. The identification of sequences occupied by NLRC5 in vivo allowed us to define a unique consensus motif for its recruitment, which diverges from that used by CIITA. Our results thus broaden our knowledge on transcriptional activity of NLRC5, highlighting its remarkable selectivity for genes encoding MHCI or related proteins and providing insights into the specificity of its recruitment. Analysis of Nlrc5 binding sites in T-cells
2015-02-27 | E-GEOD-59092 | biostudies-arrayexpress
Project description:MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) factor CIITA, which is recruited to SXY regulatory modules of MHC promoters via a DNA-binding “enhanceosome” complex. NLRC5, another NLR protein, was recently found to control transcription of MHC class I (MHCI) genes. However, detailed understanding of its target-gene specificity and mechanism of action remained lacking. We therefore performed ChIP-sequencing experiments to gain comprehensive information on NLRC5-transactivated genes. In addition to classical MHCI genes, we identified novel NLRC5-targets exclusively in the H2-Q and H2-T regions of the MHCI locus, among which the best targets were found. Investigation of cells lacking the MHCII-enhanceosome factor RFX5 demonstrated its strict requirement for NLRC5 recruitment to the SXY module conserved in MHCI genes. Furthermore, patient-derived B cell lines deficient in RFX5, RFXAP, and RFXANK corroborated importance of the enhanceosome for MHCI transactivation. Although sharing similar SXY modules and common DNA-binding factors, CIITA and NLRC5 regulate distinct genes, as shown here using double-deficient Nlrc5-/-CIIta-/- mice. The identification of sequences occupied by NLRC5 in vivo allowed us to define a unique consensus motif for its recruitment, which diverges from that used by CIITA. Our results thus broaden our knowledge on transcriptional activity of NLRC5, highlighting its remarkable selectivity for genes encoding MHCI or related proteins and providing insights into the specificity of its recruitment.
2015-02-27 | GSE59092 | GEO
Project description:NLRC5 is a member of the NLR family of proteins. The observation that NLRC5 is found in the nucleus prompted us to perform a gene array to identify putative target genes of NLRC5. We generated Jurkat T cell lines that stably express either the wild-type or mutant forms of NLRC5 harboring mutations in the nucleotide binding domain (NBD): Walker A (deficient in nucleotide binding), Walker B (deficient in nucleotide hydrolysis), and the combined Walker AB, carrying both mutations. Site-directed mutagenesis was used to create the NLRC5 NBD mutants: Walker A (K234A), Walker B (E311Q), and Walker AB (both mutations). We compared the expression profiles of Jurkat T cells expressing GFP, or the GFP-tagged wild-type, Walker A, Walker B, or Walker AB forms of NLRC5. GFP and the Walker A and Walker AB forms of NLRC5 were considered functionally inactive, while the wild-type and Walker B forms of NLRC5 were considered functionally active. These groups were used as biological replicates to assess the effect of NLRC5 activity on gene expression.
2010-07-30 | E-GEOD-22064 | biostudies-arrayexpress
Project description:NLRC5 is a member of the NLR family of proteins. The observation that NLRC5 is found in the nucleus prompted us to perform a gene array to identify putative target genes of NLRC5. We generated Jurkat T cell lines that stably express either the wild-type or mutant forms of NLRC5 harboring mutations in the nucleotide binding domain (NBD): Walker A (deficient in nucleotide binding), Walker B (deficient in nucleotide hydrolysis), and the combined Walker AB, carrying both mutations. Site-directed mutagenesis was used to create the NLRC5 NBD mutants: Walker A (K234A), Walker B (E311Q), and Walker AB (both mutations).
2010-06-30 | GSE22064 | GEO
Project description:MAIT cell activation augments adenovirus vector vaccine immunogenicity
| PRJNA666676 | ENA
Project description:Although there is significant progress in understanding the structure and function of NLRC5, a member of the NOD like receptor (NLR) family, in the context of MHC class I gene expression, the functions of NLRC5 in innate and adaptive immune responses beyond the regulation of MHC class I genes remain controversial and unresolved. In particular, the role of NLRC5 in the kidney keeps unknown. In this study, we found that NLRC5 was significantly upregulated in the kidney from mice with renal ischemia/reperfusion injury (IRI). NLRC5 deficient (NLRC5-/-) mice significantly ameliorated renal injury as evidenced by decreased serum creatinine levels, improved morphological injuries, and reduced inflammatory responses versus wild type mice. Similar protective effects were also observed in cisplatin-induced acute kidney injury (AKI). Mechanistically, NLRC5 contributed to renal injury by promoting tubular epithelial cell apoptosis and reducing inflammatory responses which is associated with, at least in part, the negative regulation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). To determine the relative contribution of NLRC5 expression by parenchymal cells or leukocytes to renal damage during IRI, we generated bone marrow (BM) chimeric mice. NLRC5-/- mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with NLRC5-/- BM, suggesting that NLRC5 signaling in renal parenchymal cells plays the dominant role in mediating renal damage. Collectively, modulation of NLRC5-mediated pathway may have important therapeutic implications for patients with AKI.
2018-01-19 | GSE109374 | GEO
Project description:Background/Objectives: Downregulation of NLRC5, the transcriptional activator of MHC class-I, results in tumor immune evasion via escape from CD8+ T cell-mediated tumor control. As NLRC5 deficiency does not abrogate CD8+ T cell development, we investigated whether NLRC5-dependent antitumor immune mechanisms are required for immune surveillance. Methods: Development of 3-methylcholanthrene (MCA)-induced endogenous fibrosarcoma was studied in Nlrc5-/- mice with Nlrc5+/+ and Rag1-/- mice serving as controls. Tumors were histologically examined. Tumor cell lines established from MCA-induced tumors were evaluated for their sensitivity to immune-mediated growth control following implantation into immunocompetent C57BL/6 and immunodeficient Rag1-/- hosts. Proteomes of MCA-induced tumors were analysed by mass spectrometry followed by pathway analysis. Results: Nlrc5-/- and Rag1-/- mice showed increased propensity to develop MCA-induced tumors with elevated growth rate compared to Nlrc5+/+ mice, and displayed significantly reduced survival. Tumors from Nlrc5+/+ and Nlrc5-/- mice, but not from Rag1-/- mice, contained necrotic areas and displayed T cell infiltration. Tumors formed by Nlrc5+/+ tumor cell lines progressed unhindered in C57BL/6 hosts that reflected their immunoedited status, whereas cell lines from Nlrc5-/- and Rag1-/- tumors were efficiently controlled, indicating their non-immunoedited status. Proteomic analysis revealed enrichment of granzyme-mediated cytolytic pathway in Nlrc5+/+ tumors that were absent in Nlrc5-/- tumors, which showed enrichment of humoral and innate immune pathways. Conclusions: Our data show that NLRC5 is required for robust tumor immune surveillance and tumor immunoediting. Compensatory humoral and innate immune mechanisms activated by the loss of NLRC5 are insufficient for cancer immune surveillance and cancer immunoediting.
2025-12-19 | PXD060523 | Pride
Project description:Inhibiting tumor cell-intrinsic UBA6 by inosine augments tumor immunogenicity
| PRJNA864795 | ENA
Project description:A mutation that results in tumor rejection activity in a neoepitope (which is a poor binder of Kd) influences the immunogenicity of the tumor as a whole. Our results demonstrate the activity in vivo of a poorly-MHC I-binding cancer neoepitope.
2021-05-31 | GSE171100 | GEO