DSpace Community:http://hdl.handle.net/10722/385512024-03-29T15:16:25Z2024-03-29T15:16:25ZFunctions of double‐negative B cells in autoimmune diseases, infections, and cancersChung, Michael King YungGong, LanqiKwong, Dora Lai WanLee, Victor Ho FunLee, Ann Wing MuiGuan, Xin YuanKam, Ngar WoonDai, Weihttp://hdl.handle.net/10722/3408452024-03-11T10:47:44Z2023-06-05T00:00:00ZTitle: Functions of double‐negative B cells in autoimmune diseases, infections, and cancers
Authors: Chung, Michael King Yung; Gong, Lanqi; Kwong, Dora Lai Wan; Lee, Victor Ho Fun; Lee, Ann Wing Mui; Guan, Xin Yuan; Kam, Ngar Woon; Dai, Wei
Abstract: <p>Most mature B cells can be divided into four subtypes based on the expression of the surface markers IgD and CD27: IgD<sup>+</sup>CD27<sup>−</sup> naïve B cells, IgD<sup>+</sup>CD27<sup>+</sup> unswitched memory B cells, IgD<sup>−</sup>CD27<sup>+</sup> switched memory B cells, and IgD<sup>−</sup>CD27<sup>−</sup> double-negative (DN) B cells. Despite their small population size in normal peripheral blood, DN B cells play integral roles in various diseases. For example, they generate autoimmunity in autoimmune conditions, while these cells may generate both autoimmune and antipathogenic responses in COVID-19, or act in a purely antipathogenic capacity in malaria. Recently, DN B cells have been identified in nasopharyngeal carcinoma and non-small-cell lung cancers, where they may play an immunosuppressive role. The distinct functions that DN B cells play in different diseases suggest that they are a heterogeneous B-cell population. Therefore, further study of the mechanisms underlying the involvement of DN B cells in these diseases is essential for understanding their pathogenesis and the development of therapeutic strategies. Further research is thus warranted to characterize the DN B-cell population in detail.</p>2023-06-05T00:00:00ZGenome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasisWen, WLiao, LDai, WZheng, CCTan, XPHe, YZhang, QHHuang, ZHChen, WYQin, YRChen, KSHe, MLLaw, SLung, MLHe, QYLi, Bhttp://hdl.handle.net/10722/3408442024-03-11T10:47:44Z2023-05-04T00:00:00ZTitle: Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis
Authors: Wen, W; Liao, L; Dai, W; Zheng, CC; Tan, XP; He, Y; Zhang, QH; Huang, ZH; Chen, WY; Qin, YR; Chen, KS; He, ML; Law, S; Lung, ML; He, QY; Li, B
Abstract: <h3>Background</h3><p>Metastasis is one of the most lethal hallmarks of esophageal squamous cell carcinoma (ESCC), yet the mechanisms remain unclear due to a lack of reliable experimental models and systematic identification of key drivers. There is urgent need to develop useful therapies for this lethal disease.</p><h3>Methods</h3><p>A genome-wide CRISPR/Cas9 screening, in combination with gene profiling of highly invasive and metastatic ESCC sublines, as well as PDX models, was performed to identify key regulators of cancer metastasis. The Gain- and loss-of-function experiments were taken to examine gene function. Protein interactome, RNA-seq, and whole genome methylation sequencing were used to investigate gene regulation and molecular mechanisms. Clinical significance was analyzed in tumor tissue microarray and TCGA databases. Homology modeling, modified ELISA, surface plasmon resonance and functional assays were performed to identify lead compound which targets MEST to suppress cancer metastasis.</p><h3>Findings</h3><p>High MEST expression was associated with poor patient survival and promoted cancer invasion and metastasis in ESCC. Mechanistically, MEST activates SRCIN1/RASAL1-ERK-snail signaling by interacting with PURA. miR-449a was identified as a direct regulator of MEST, and hypermethylation of its promoter led to MEST upregulation, whereas systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity. Furthermore, molecular docking and computational screening in a small-molecule library of 1,500,000 compounds and functional assays showed that G699-0288 targets the MEST-PURA interaction and significantly inhibits cancer metastasis.</p><h3>Interpretation</h3><p>We identified the MEST-PURA-SRCIN1/RASAL1-ERK-snail signaling cascade as an important mechanism underlying cancer metastasis. Blockade of MEST-PURA interaction has therapeutic potential in management of cancer metastasis.</p>2023-05-04T00:00:00ZEpigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinomaChow, LKYChung, DLSTao, LHChan, KFTung, SYNgan, RKCNg, WTLee, AWMYau, CCKwong, DLWLee, VHFLam, KOLiu, JYChen, HLDai, WLung, MLhttp://hdl.handle.net/10722/3408422024-03-11T10:47:42Z2023-02-28T00:00:00ZTitle: Epigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma
Authors: Chow, LKY; Chung, DLS; Tao, LH; Chan, KF; Tung, SY; Ngan, RKC; Ng, WT; Lee, AWM; Yau, CC; Kwong, DLW; Lee, VHF; Lam, KO; Liu, JY; Chen, HL; Dai, W; Lung, ML
Abstract: <h3>Background</h3><p>Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in nasopharyngeal carcinoma (NPC).</p><h3>Methods</h3><p>To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data.</p><h3>Findings</h3><p>In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r<sup>2</sup> = 0.55).</p><h3>Interpretation</h3><p>Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion.</p>2023-02-28T00:00:00ZNasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interactionGong, LanqiLuo, JieZhang, YuYang, YumaLi, ShanshanFang, XiaonaZhang, BaifengHuang, JiaoChow, Larry Ka YueChung, DittmanHuang, JinlinHuang, CuicuiLiu, QinBai, LuTiu, Yuen ChakWu, PinganWang, YanTsao, George Sai WahKwong, Dora Lai WanLee, Anne Wing MuiDai, WeiGuan, Xin Yuanhttp://hdl.handle.net/10722/3408372024-03-11T10:47:40Z2023-04-06T00:00:00ZTitle: Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction
Authors: Gong, Lanqi; Luo, Jie; Zhang, Yu; Yang, Yuma; Li, Shanshan; Fang, Xiaona; Zhang, Baifeng; Huang, Jiao; Chow, Larry Ka Yue; Chung, Dittman; Huang, Jinlin; Huang, Cuicui; Liu, Qin; Bai, Lu; Tiu, Yuen Chak; Wu, Pingan; Wang, Yan; Tsao, George Sai Wah; Kwong, Dora Lai Wan; Lee, Anne Wing Mui; Dai, Wei; Guan, Xin Yuan
Abstract: <p>Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.</p>2023-04-06T00:00:00Z