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关键词： HLA-DRB1*11:340   HLA   novel allele   sequencing-based typing  

摘要： HLA-DRB1*11:340 differs from HLA-DRB1*11:01:01:01 by one nucleotide substitution in codon 36 in exon 2.

关键词： anti-PD-1   bioinformatic analysis   colorectal cancer   combinatorial immunotherapy   interferon-alpha   RIG-I  

摘要： BackgroundsImmunotherapy is a promising and effective approach that has achieved significant curative effects in colorectal cancer (CRC). Recently, retinoic acid-inducible gene I (RIG-I) has been shown to play a critical role in tumor immunity. However, the correlation between RIG-I and immunotherapy in CRC remains ***-I expression was measured in CRC and normal samples based on analysis of the public databases, a tissue microarray, and CRC cell lines. The correlation between RIG-I and immune microenvironment was explored using well-established biological algorithms and in vitro and in vivo *** discovered that RIG-I expression was downregulated in CRC compared with normal samples. The bioinformatic algorithms indicated that high RIG-I-expressing samples showed a positive correlation with IFN-alpha response and enrichment of antitumor immune cells, especially CD8+ T cells. Furthermore, knockdown of RIG-I expression efficiently reduced the cell death, STAT1 phosphorylation, and CXCL10/11 expression induced by IFN-alpha in CRC cells. Finally, an in vivo study showed that the infiltration of CD3+ CD8+ T cells was significantly decreased in the RIG-I knockout group. An animal model further confirmed that the inhibition of tumor growth induced by IFN-alpha plus anti-PD-1 therapy was dependent on RIG-I ***-I is a promising biomarker for CRC immunotherapy, which provides a novel concept for combinatorial immunotherapy.

关键词： HLA-B*35:186   sequence-based typing   the novel allele  

摘要： HLA-B*35:186 differs from HLA-B*35:01:01:01 by 12 nucleotide substitutions in exon 2.

关键词： aryl hydrocarbon receptor   cancer   interferon gamma   tumor immunity  

摘要： While immunotherapy has shown some efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation, the AhR, a known but counterintuitive mediator of immunosuppression (interferon (IFN)-gamma), and regulation of two immune checkpoints (PD-L1 and IDO). AhR gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk and scRNA sequencing of LUADs and tumor-infiltrating T cells were used to map out a signaling pathway leading from IFN-gamma through the AhR to JAK/STAT, PD-L1, IDO, and tumor-mediated immunosuppression. The data demonstrate that: (1) IFN-gamma activation of the JAK/STAT pathway leading to PD-L1 and IDO1 up-regulation is mediated by the AhR in murine and human LUAD cells, (2) AhR-driven IDO1 induction results in the production of Kynurenine (Kyn), an AhR ligand, which likely mediates an AhR -> IDO1 -> Kyn -> AhR amplification loop, (3) transplantation of AhR-knockout LUAD cells results in long-term tumor immunity in most recipients. (4) The 23% of AhR-knockout tumors that do grow do so at a much slower pace than controls and exhibit higher densities of CD8+ T cells expressing markers of immunocompetence, increased activity, and increased cell-cell communication. The data definitively link the AhR to IFN-gamma-induced JAK/STAT pathway and immune checkpoint-mediated immunosuppression and support the targeting of the AhR in the context of LUAD.

摘要： Hypoimmunogenic universal induced pluripotent stemn (iPS) cells were generated through the targeted disruption of key genes, including human leukocyte antigen (HLA)-A, HLA-B and HLA-DR alpha (DRA), using the CRISPR-Cas9 system. This approach aimed to minimize immune recognition and enhance the potential of iPS cells for allogeneic therapy. Heterozygous iPS cells were used for guide RNA design and validation to facilitate the knockout (KO) of the HLA-A, HLA-B and HLA-DRA genes. The electroporation of iPS cells using the selected guide RNAs enabled the generation of triple-KO iPS cells, followed by single-cell cloning for clone selection. Clone A7, an iPS cell with targeted KOs of the HLA-A, HLA-B and HLA-DRA genes, was identified as the final candidate. Messenger RNA analysis revealed robust expression of pluripotency markers, such as octamer-binding transcription factor 4, sex-determining region Y box 2, Kr & uuml;ppel-like factor 4, Lin-28 homolog A and Nanog homeobox, while protein expression assays confirmed the presence of octamer-binding transcription factor 4, stage-specific embryonic antigen 4, Nanog homeobox and tumor rejection antigen 1-60. A karyotype examination revealed no anomalies, and three-germ layer differentiation assays confirmed the differentiation potential. After interferon gamma stimulation, the gene-corrected clone A7 lacked HLA-A, HLA-B and HLA-DR protein expression. Immunogenicity testing further confirmed the hypoimmunogenicity of clone A7, which was evidenced by the absence of proliferation in central memory T cells and effector memory T cells. In conclusion, clone A7, a triple-KO iPS cell clone that demonstrates immune evasion properties, retained its intrinsic iPS cell characteristics and exhibited no immunogenicity.

关键词： BCL6   GPR61   IL-1 beta   osteoarthritis  

摘要： Osteoarthritis (OA) is the most common joint disease and its pathogenic mechanism remains to be ensured. This study focused on the regulatory relation between B-cell lymphoma 6 (BCL6) and G-protein-coupled receptor 61 (GPR61) underlying IL-1 beta in OA. Real-time quantitative polymerase chain reaction and western blot were performed for mRNA and protein detection. Oxidative injury was assessed by reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) via kits. Fe2+ level was measured via an iron assay kit. Relation analysis between BCL6 and GPR61 was implemented employing ChIP assay and dual-luciferase reporter assay. GPR61 was downregulated in OA samples and IL-1 beta-induced C28/I2 cells. IL-1 beta-induced cell inflammation, extracellular matrix (ECM) degradation, oxidative stress, and ferroptosis were all returned by overexpression of GPR61. BCL6 downregulation was detected in OA patients and IL-1 beta-exposed C28/I2 cells. BCL6 could promote the transcription of GPR61. BCL6 suppressed IL-1 beta-induced OA progression by upregulating GPR61. The BCL6/GPR61 axis activated the PKA/CREB pathway in IL-1 beta-treated C28/I2 cells. The above results suggested that BCL6 mitigated OA progression induced by IL-1 beta by enhancing transcription of GPR61. BCL6/GPR61/PKA/CREB axis may be considered as a novel regulatory mechanism in OA, and BCL6 has the potential to act as a novel target for OA.

关键词： HLA-A*02:1133   NGS   novel allele  

摘要： HLA-A*02:1133 differs from HLA-A*02:01:01:01 by a single nucleotide substitution at position 37 C>T in exon 1.

关键词： Crohn's disease   Pediatrics   Anti-TNF therapy   Steroid-free remission   Biomarkers