Clinical & Translational Immunology最新文献

{"title":"Maintenance of caecal homeostasis by diverse adaptive immune cells in the rhesus macaque","authors":"Xaquin Castro Dopico,&nbsp;Mariia Guryleva,&nbsp;Marco Mandolesi,&nbsp;Martin Corcoran,&nbsp;Jonathan M Coquet,&nbsp;Ben Murrell,&nbsp;Gunilla B Karlsson Hedestam","doi":"10.1002/cti2.1508","DOIUrl":"https://doi.org/10.1002/cti2.1508","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The caecum bridges the small and large intestine and plays a front-line role in discriminating gastrointestinal antigens. Although dysregulated in acute and chronic conditions, the tissue is often overlooked immunologically.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this issue, we applied single-cell transcriptomic-V(D)J sequencing to FACS-isolated CD45⁺ caecal patch/lamina propria leukocytes from a healthy (5-year-old) female rhesus macaque <i>ex vivo</i> and coupled these data to VDJ deep sequencing reads from haematopoietic tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found caecal NK cells and ILC3s to co-exist with a spectrum of effector T cells partially derived from <i>SOX4</i>⁺ recent thymic emigrants. Tolerogenic Vγ8Vδ1-T cells, plastic CD4⁺ T helper cells and <i>GZMK</i>⁺<i>EOMES</i>⁺ and <i>TMIGD2</i>⁺ tissue-resident memory CD8⁺ T cells were present and differed metabolically. An <i>IL13</i>⁺<i>GATA3</i>⁺ Th₂ subset expressing eicosanoid pathway enzymes was accompanied by <i>IL1RL1</i>⁺<i>GATA3</i>⁺ regulatory T cells and a minor proportion of IgE⁺ plasma cells (PCs), illustrating tightly regulated type 2 immunity devoid of ILC2s. In terms of B lymphocyte lineages, caecal patch antigen-presenting memory B cells sat alongside germinal centre cells undergoing somatic hypermutation and differentiation into <i>IGF1</i>⁺ PCs. Prototypic gene expression signatures decreased across PC clusters, and notably, expanded IgA clonotypes could be traced in VDJ deep sequencing reads from additional compartments, including the bone marrow, supporting that these cells contribute a steady stream of systemic antibodies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The data advance our understanding of caecal immunological function, revealing processes involved in barrier maintenance and molecular networks relevant to disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140818974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimisation of a primary human CAR-NK cell manufacturing pipeline","authors":"Aline Pfefferle,&nbsp;Julian Contet,&nbsp;Kahlia Wong,&nbsp;Charlotte Chen,&nbsp;Els Verhoeyen,&nbsp;Chloe K Slichter,&nbsp;Kimberly S Schluns,&nbsp;Joseph Cursons,&nbsp;Richard Berry,&nbsp;Iva Nikolic,&nbsp;Jai Rautela,&nbsp;Nicholas D Huntington","doi":"10.1002/cti2.1507","DOIUrl":"https://doi.org/10.1002/cti2.1507","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Autologous chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies achieves long-term disease remission in a high fraction of patients and has triggered intense research into translating this successful approach into additional cancer types. However, the complex logistics involved in autologous CAR-T manufacturing, the compromised fitness of patient-derived T cells, the high rates of serious toxicities and the overall cost involved with product manufacturing and hospitalisation have driven innovation to overcome such hurdles. One alternative approach is the use of allogeneic natural killer (NK) cells as a source for CAR-NK cell therapy. However, this source has traditionally faced numerous manufacturing challenges.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this, we have developed an optimised expansion and transduction protocol for primary human NK cells primed for manufacturing scaling and clinical evaluation. We have performed an in-depth comparison of primary human NK cell sources as a starting material by characterising their phenotype, functionality, expansion potential and transduction efficiency at crucial timepoints of our CAR-NK manufacturing pipeline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified adult peripheral blood-derived NK cells to be the superior source for generating a CAR-NK cell product because of a higher maximum yield of CAR-expressing NK cells combined with potent natural, as well as CAR-mediated anti-tumor effector functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our optimised manufacturing pipeline dramatically improves lentiviral transduction efficiency of primary human NK cells. We conclude that the exponential expansion pre- and post-transduction and high on-target cytotoxicity make peripheral blood-derived NK cells a feasible and attractive CAR-NK cell product for clinical utility.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140818975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chitinase 3-like 1 expression associated with lymphatic metastasis and prognosis in urothelial carcinoma of the bladder","authors":"Bo Wang,&nbsp;Ke Chen,&nbsp;Mingchao Gao,&nbsp;Xi Sun,&nbsp;Wang He,&nbsp;Junyu Chen,&nbsp;Wenjuan Yang,&nbsp;Tenghao Yang,&nbsp;Haide Qin,&nbsp;Honglian Ruan,&nbsp;Hao Huang,&nbsp;Tianxin Lin,&nbsp;Jian Huang","doi":"10.1002/cti2.1505","DOIUrl":"https://doi.org/10.1002/cti2.1505","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Lymphatic metastasis, an early stage of the metastasis process, is associated with adverse clinical outcomes in urothelial carcinoma of the bladder (UCB). However, the role of inflammation in triggering lymphatic metastasis remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed an RNA-sequencing cohort (<i>n</i> = 50) from Sun Yat-Sen Memorial Hospital (SYMH) to identify the most highly upregulated inflammatory gene associated with lymphatic metastasis. Using immunohistochemistry and immunofluorescence analyses, we validated the association of the identified molecule with clinical features and prognosis in an independent UCB cohort (<i>n</i> = 244) from SYMH. We also analysed TCGA-BLCA cohort (<i>n</i> = 408) to identify its potential biological pathways and immune landscape.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In our study, chitinase 3-like 1 (CHI3L1) emerged as a significantly overexpressed proinflammatory mediator in UCB tissues with lymphatic metastasis compared to those without lymphatic metastasis (81.1% vs. 47.8%, <i>P</i> &lt; 0.001). Within UCB tissues, CHI3L1 was expressed in both stromal cells (52.8%) and tumor cells (7.3%). Moreover, CHI3L1⁺ stromal cells, but not tumor cells, exhibited independent prognostic significance for both overall survival (<i>P</i> &lt; 0.001) and recurrence-free survival (<i>P</i> = 0.006). CHI3L1⁺ stromal cells were positively associated with D2-40⁺ lymphatic vessel density (<i>P</i> &lt; 0.001) and the immunosuppressive PD-L1/PD-1/CD8 axis in UCB tissues (all <i>P</i> &lt; 0.05). A bioinformatics analysis also identified a positive association between CHI3L1 expression and lymphangiogenesis or immunosuppression pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study established a clear association between stromal CHI3L1 expression and lymphatic metastasis, suggesting that stromal CHI3L1 expression is a potential prognostic marker for bladder cancer patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2-infected human airway epithelial cell cultures uniquely lack interferon and immediate early gene responses caused by other coronaviruses","authors":"Ying Wang,&nbsp;Melissa Thaler,&nbsp;Clarisse Salgado-Benvindo,&nbsp;Nathan Ly,&nbsp;Anouk A Leijs,&nbsp;Dennis K Ninaber,&nbsp;Philip M Hansbro,&nbsp;Fia Boedijono,&nbsp;Martijn J van Hemert,&nbsp;Pieter S Hiemstra,&nbsp;Anne M van der Does,&nbsp;Alen Faiz","doi":"10.1002/cti2.1503","DOIUrl":"https://doi.org/10.1002/cti2.1503","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of a class of highly pathogenic coronaviruses. The large family of coronaviruses, however, also includes members that cause only mild symptoms, like human coronavirus-229E (HCoV-229E) or OC43 (HCoV-OC43). Unravelling how molecular (and cellular) pathophysiology differs between highly and low pathogenic coronaviruses is important for the development of therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we analysed the transcriptome of primary human bronchial epithelial cells (PBEC), differentiated at the air–liquid interface (ALI) after infection with SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV and HCoV-229E using bulk RNA sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ALI-PBEC were efficiently infected by all viruses, and SARS-CoV, MERS-CoV and HCoV-229E infection resulted in a largely similar transcriptional response. The response to SARS-CoV-2 infection differed markedly as it uniquely lacked the increase in expression of immediate early genes, including <i>FOS</i>, <i>FOSB</i> and <i>NR4A1</i> that was observed with all other coronaviruses. This finding was further confirmed in publicly available experimental and clinical datasets. Interfering with NR4A1 signalling in Calu-3 lung epithelial cells resulted in a 100-fold reduction in extracellular RNA copies of SARS-CoV-2 and MERS-CoV, suggesting an involvement in virus replication. Furthermore, a lack in induction of interferon-related gene expression characterised the main difference between the highly pathogenic coronaviruses and low pathogenic viruses HCoV-229E and HCoV-OC43.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results demonstrate a previously unknown suppression of a host response gene set by SARS-CoV-2 and confirm a difference in interferon-related gene expression between highly pathogenic and low pathogenic coronaviruses.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1503","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chimeric antigen receptor T cells in the fast lane among autoimmune disease therapies","authors":"Zhoujie Ding,&nbsp;David Tarlinton","doi":"10.1002/cti2.1502","DOIUrl":"https://doi.org/10.1002/cti2.1502","url":null,"abstract":"<p>In this commentary, we highlight recent studies demonstrating the feasibility and promise of chimeric antigen receptor (CAR) T-cell therapy in treating a number of autoimmune disorders including systemic lupus erythematosus and compare CAR T cells to other therapies aimed at depleting B-lineage cells in treating such diseases.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140546872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD177 drives the transendothelial migration of Treg cells enriched in human colorectal cancer","authors":"Shouyu Ke,&nbsp;Yi Lei,&nbsp;Yixian Guo,&nbsp;Feng Xie,&nbsp;Yimeng Yu,&nbsp;Haigang Geng,&nbsp;Yiqing Zhong,&nbsp;Danhua Xu,&nbsp;Xu Liu,&nbsp;Fengrong Yu,&nbsp;Xiang Xia,&nbsp;Zizhen Zhang,&nbsp;Chunchao Zhu,&nbsp;Wei Ling,&nbsp;Bin Li,&nbsp;Wenyi Zhao","doi":"10.1002/cti2.1506","DOIUrl":"https://doi.org/10.1002/cti2.1506","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Regulatory T (Treg) cells regulate immunity in autoimmune diseases and cancers. However, immunotherapies that target tumor-infiltrating Treg cells often induce unwanted immune responses and tissue inflammation. Our research focussed on exploring the expression pattern of CD177 in tumor-infiltrating Treg cells with the aim of identifying a potential target that can enhance immunotherapy effectiveness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single-cell RNA sequencing (scRNA-seq) data and survival data were obtained from public databases. Twenty-one colorectal cancer patient samples, including fresh tumor tissues, peritumoral tissues and peripheral blood mononuclear cells (PBMCs), were analysed using flow cytometry. The transendothelial activity of CD177⁺ Treg cells was substantiated using <i>in vitro</i> experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ScRNA-seq and flow cytometry results indicated that CD177 was exclusively expressed in intratumoral Treg cells. CD177⁺ Treg cells exhibited greater activation status and expressed elevated Treg cell canonical markers and immune checkpoint molecules than CD177⁻ Treg cells. We further discovered that both intratumoral CD177⁺ Treg cells and CD177-overexpressing induced Treg (iTreg) cells had lower levels of PD-1 than their CD177⁻ counterparts. Moreover, CD177 overexpression significantly enhanced the transendothelial migration of Treg cells <i>in vitro</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results demonstrated that Treg cells with higher CD177 levels exhibited an enhanced activation status and transendothelial migration capacity. Our findings suggest that CD177 may serve as an immunotherapeutic target and that overexpression of CD177 may improve the efficacy of chimeric antigen receptor T (CAR-T) cell therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140541096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of distinct immune signatures in inclusion body myositis by peripheral blood immunophenotyping using machine learning models","authors":"Emily McLeish,&nbsp;Anuradha Sooda,&nbsp;Nataliya Slater,&nbsp;Kelly Beer,&nbsp;Ian Cooper,&nbsp;Frank L Mastaglia,&nbsp;Merrilee Needham,&nbsp;Jerome D Coudert","doi":"10.1002/cti2.1504","DOIUrl":"https://doi.org/10.1002/cti2.1504","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Inclusion body myositis (IBM) is a progressive late-onset muscle disease characterised by preferential weakness of quadriceps femoris and finger flexors, with elusive causes involving immune, degenerative, genetic and age-related factors. Overlapping with normal muscle ageing makes diagnosis and prognosis problematic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We characterised peripheral blood leucocytes in 81 IBM patients and 45 healthy controls using flow cytometry. Using a random forest classifier, we identified immune changes in IBM compared to HC. K-means clustering and the random forest one-versus-rest model classified patients into three immunophenotypic clusters. Functional outcome measures including mTUG, 2MWT, IBM-FRS, EAT-10, knee extension and grip strength were assessed across clusters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The random forest model achieved a 94% AUC ROC with 82.76% specificity and 100% sensitivity. Significant differences were found in IBM patients, including increased CD8⁺ T-bet⁺ cells, CD4⁺ T cells skewed towards a Th1 phenotype and altered γδ T cell repertoire with a reduced proportion of Vγ9⁺Vδ2⁺ cells. IBM patients formed three clusters: (i) activated and inflammatory CD8⁺ and CD4⁺ T-cell profile and the highest proportion of anti-cN1A-positive patients in cluster 1; (ii) limited inflammation in cluster 2; (iii) highly differentiated, pro-inflammatory T-cell profile in cluster 3. Additionally, no significant differences in patients' age and gender were detected between immunophenotype clusters; however, worsening trends were detected with several functional outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings unveil distinct immune profiles in IBM, shedding light on underlying pathological mechanisms for potential immunoregulatory therapeutic development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140345595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway","authors":"Jingjing Pu,&nbsp;Amit Sharma,&nbsp;Ting Liu,&nbsp;Jian Hou,&nbsp;Ingo GH Schmidt-Wolf","doi":"10.1002/cti2.1500","DOIUrl":"https://doi.org/10.1002/cti2.1500","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various <i>in vitro</i> methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1500","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring NK cell receptor dynamics in paediatric leukaemias: implications for immunotherapy and prognosis","authors":"Cui Tu,&nbsp;Irina Buckle,&nbsp;Ingrid Leal Rojas,&nbsp;Gustavo Rodrigues Rossi,&nbsp;David P Sester,&nbsp;Andrew S Moore,&nbsp;Kristen Radford,&nbsp;Camille Guillerey,&nbsp;Fernando Souza-Fonseca-Guimaraes","doi":"10.1002/cti2.1501","DOIUrl":"https://doi.org/10.1002/cti2.1501","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Immunotherapies targeting natural killer (NK) cell receptors have shown promise against leukaemia. Unfortunately, cancer immunosuppressive mechanisms that alter NK cell phenotype prevent such approaches from being successful. The study utilises advanced cytometry to examine how cancer immunosuppressive pathways affect NK cell phenotypic changes in clinical samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we conducted a high-dimensional examination of the cell surface expression of 16 NK cell receptors in paediatric patients with acute myeloid leukaemia and acute lymphoblastic leukaemia, as well as in samples of non-age matched adult peripheral blood (APB) and umbilical cord blood (UCB). An unsupervised analysis was carried out in order to identify NK cell populations present in paediatric leukaemias.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed that leukaemia NK cells clustered together with UCB NK cells and expressed relatively higher levels of the NKG2A receptor compared to APB NK cells. In addition, CD56^dimCD16⁺CD57⁻ NK cells lacking NKG2A expression were mainly absent in paediatric leukaemia patients. However, CD56^br NK cell populations expressing high levels of NKG2A were highly represented in paediatric leukaemia patients. NKG2A expression on leukaemia NK cells was found to be positively correlated with the expression of its ligand, suggesting that the NKG2A-HLA-E interaction may play a role in modifying NK cell responses to leukaemia cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We provide an in-depth analysis of NK cell populations in paediatric leukaemia patients. These results support the development of immunotherapies targeting immunosuppressive receptors, such as NKG2A, to enhance innate immunity against paediatric leukaemia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140192318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD39 expression defines exhausted CD4+ T cells associated with poor survival and immune evasion in human gastric cancer","authors":"Zhen-quan Duan,&nbsp;Yu-xian Li,&nbsp;Yuan Qiu,&nbsp;Yang Shen,&nbsp;Ying Wang,&nbsp;Yuan-yuan Zhang,&nbsp;Bao-hang Zhu,&nbsp;Xiao-hong Yu,&nbsp;Xue-ling Tan,&nbsp;Weisan Chen,&nbsp;Yuan Zhuang,&nbsp;Ping Cheng,&nbsp;Wei-jun Zhang,&nbsp;Quan-ming Zou,&nbsp;Dai-yuan Ma,&nbsp;Liu-sheng Peng","doi":"10.1002/cti2.1499","DOIUrl":"https://doi.org/10.1002/cti2.1499","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>CD4⁺ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4⁺ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4⁺ T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4⁺ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In comparison with CD4⁺ T cells from the non-tumor tissues, significantly more GC-infiltrating CD4⁺ T cells expressed CD39. Most GC-infiltrating CD39⁺CD4⁺ T cells exhibited CD45RA⁻CCR7⁻ effector–memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39⁻CD4⁺ counterparts. Moreover, <i>ex vivo</i> inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39⁺CD4⁺ T cells were positively associated with disease progression and patients' poorer overall survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study demonstrates that CD39 expression defines GC-infiltrating CD4⁺ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1499","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140145681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}