Clinical & Translational Immunology最新文献

{"title":"Biomarkers to predict and diagnose pulmonary complications in children post haematopoietic stem cell transplant","authors":"Hannah Walker,&nbsp;Gabrielle M Haeusler,&nbsp;Theresa Cole,&nbsp;Melanie Neeland,&nbsp;Diane Hanna,&nbsp;Shivanthan Shanthikumar","doi":"10.1002/cti2.70002","DOIUrl":"https://doi.org/10.1002/cti2.70002","url":null,"abstract":"<p>Objectives. Haematopoietic cell transplant (HCT) is a cellular therapy for a group of high-risk children with cancer, immunodeficiency and metabolic disorders. Whilst curative for a child's underlying condition, HCT has significant risks associated, including lung injury. These complications are associated with increased post HCT mortality and require improved methods of risk stratification, diagnosis and treatment. Methods. Biomarkers measured in bronchoalveolar fluid and peripheral blood have been identified for both acute and chronic lung injury post HCT.This review evaluates the current research available investigating the use of these biomarkers to improve clinical care, with a focus on the paediatric cohort. Results. Elevated levels of cytokines such as IL-6, IL-8, G-CSF and TNF were identified as potential predictive biomarkers for the development of post HCT lung disease. The pulmonary microbiome was found to have strong potential as a biomarker pre and post HCT for the development of pulmonary complications. General limitations of the studies identified were study design, retrospective or single centre and not exclusively performed in the paediatric population. Conclusion. To translate biomarker discovery into clinical implementation further research is required, utilising larger cohorts of children in prospective trials to validate these biomarkers and determine how they can be translated into better outcomes for children post HCT.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244946","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":"The Omega-6 Lipid pathway shift is associated with neutrophil influx and structural lung damage in early cystic fibrosis lung disease","authors":"Lisa JM Slimmen,&nbsp;Jelle Y Broos,&nbsp;Badies HAN Manaï,&nbsp;Silvia C Estevão,&nbsp;Martin Giera,&nbsp;Gijs Kooij,&nbsp;Wendy WJ Unger,&nbsp;Hettie M Janssens","doi":"10.1002/cti2.70000","DOIUrl":"https://doi.org/10.1002/cti2.70000","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In cystic fibrosis (CF), an imbalanced lipid metabolism is associated with lung inflammation. Little is known about the role that specific lipid mediators (LMs) exert in CF lung inflammation, and whether their levels change during early disease progression. Therefore, we measured airway LM profiles of young CF patients, correlating these with disease-associated parameters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Levels of omega (ω)-3/6 PUFAs and their LM derivatives were determined in bronchoalveolar lavage fluid (BALF) of children with CF ages 1–5 using a targeted high-performance liquid chromatography–tandem mass spectrometry approach. Hierarchical clustering analysis was performed on relative LM levels. Individual relative LM levels were correlated with neutrophilic inflammation (BALF %Neu) and structural lung damage (PRAGMA-CF %Disease). Significant correlations were included in a backward multivariate linear regression model to identify the LMs that are best related to disease progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 65 BALF samples were analysed for ω-3/6 lipid content. LM profiles clustered into an arachidonic acid (AA)-enriched and a linoleic acid (LA)-enriched sample cluster. AA derivatives like 17-OH-DH-HETE, 5-HETE, 5,15-diHETE, 15-HETE, 15-KETE, LTB₄ and 6-trans-LTB₄ positively correlated with BALF %Neu and/or PRAGMA %Dis. Contrastingly, 9-HoTrE and the LA derivatives 9-HoDE, 9(10)-EpOME, 9(10)-DiHOME, 13-HoDE, 13-oxoODE and 12(13)-EpOME negatively correlated with BALF %Neu and/or PRAGMA %Dis. 6-trans-LTB₄ was the strongest predictor for BALF %Neu. 5-HETE and 15-KETE contributed most to PRAGMA %Dis prediction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our data provide more insight into the lung lipidome of infants with CF, and show that a shift from LA derivatives to AA derivatives in BALF associates with early CF lung disease progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244504","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":"Siglec-7 and Siglec-9 expression in primary triple negative and oestrogen receptor positive breast cancer and in vitro signalling","authors":"Eline JH van Houtum,&nbsp;Anne HC Valk,&nbsp;Daniel Granado,&nbsp;Jasper Lok,&nbsp;Lune van den Bogaard,&nbsp;Naomi Remkes,&nbsp;Jesper van Eck van der Sluijs,&nbsp;Paul N Span,&nbsp;Lenneke AM Cornelissen,&nbsp;Gosse J Adema","doi":"10.1002/cti2.1524","DOIUrl":"https://doi.org/10.1002/cti2.1524","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>PD-1/PD-L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec-7 and Siglec-9 as novel ITIM-bearing inhibitory immune checkpoint receptors similar to PD-1, but expressed on a broader range of immune cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We assessed Siglec-7 and Siglec-9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line-induced signalling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We report that Siglec-7 and Siglec-9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec-7 was observed on myeloid cells, T cells, and NK cells and Siglec-9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec-7 and Siglec-9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec-7 and Siglec-9 ligands were higher on <i>in vitro</i> cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec-7 reporter cells, we showed the induction of Siglec-7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec-7 signalling is directly related to Siglec-7 ligand expression levels of breast cancer cell lines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1524","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152162","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":"Schistosoma excretory/secretory products: an untapped library of tolerogenic immunotherapeutics against food allergy","authors":"Madeleine Rogers,&nbsp;Sandip Kamath,&nbsp;Donald McManus,&nbsp;Malcolm Jones,&nbsp;Catherine Gordon,&nbsp;Severine Navarro","doi":"10.1002/cti2.70001","DOIUrl":"https://doi.org/10.1002/cti2.70001","url":null,"abstract":"<p>Food allergy (FA) is considered the ‘second wave’ of the allergy epidemic in developed countries after asthma and allergic rhinitis with a steadily growing burden of 40%. The absence of early childhood pathogen stimulation embodied by the hygiene hypothesis is one explanation, and in particular, the eradication of parasitic helminths could be at play. Infections with parasites <i>Schistosoma</i> spp. have been found to have a negative correlation with allergic diseases. Schistosomes induce regulatory responses to evade immune detection and ensure their long-term survival. This is achieved via excretory/secretory (E/S) products, consisting of proteins, lipids, metabolites, nucleic acids and extracellular vesicles, representing an untapped therapeutic avenue for the treatment of FA without the unpleasant side-effects and risks associated with live infection. Schistosome-derived immunotherapeutic development is in its infancy and novel discoveries are heavily technology dependent; thus, it is essential to better understand how newly identified molecules interact with host immune systems to ensure safety and successful translation. This review will outline the identified <i>Schistosoma</i>-derived E/S products at all life cycle stages and discuss known mechanisms of action and their ability to suppress FA.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100324","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":"Anti-signal recognition particle antibodies induce cardiac diastolic dysfunction via oxidative stress injury","authors":"Hao Zhang,&nbsp;Yunjing Shi,&nbsp;Yingze Fan,&nbsp;Dehao Zhu,&nbsp;Zeping Qiu,&nbsp;Huihui Chi,&nbsp;Qiongyi Hu,&nbsp;Liangzhe Xie,&nbsp;Yue Sun,&nbsp;Honglei Liu,&nbsp;Xiaobing Cheng,&nbsp;Junna Ye,&nbsp;Hui Shi,&nbsp;Zhuochao Zhou,&nbsp;Jianfen Meng,&nbsp;Jialin Teng,&nbsp;Chengde Yang,&nbsp;Wei Jin,&nbsp;Yutong Su","doi":"10.1002/cti2.1525","DOIUrl":"https://doi.org/10.1002/cti2.1525","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Anti-signal recognition particle (SRP) antibodies, markers of immune-mediated necrotising myopathy, are reportedly related to cardiac involvement; however, whether they are pathogenic to the myocardium remains unclear. We aimed, therefore, to explore the pathogenicity of anti-SRP antibodies against the myocardium through <i>in vivo</i> and <i>in vitro</i> studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Total immunoglobulin G (IgG), purified from patients with positive anti-SRP antibodies, was passively transferred into C57BL/6 mice. Cardiac function was evaluated via echocardiography and the ventricular pressure–volume loop; cardiac histological changes were analysed using haematoxylin–eosin staining, picrosirius red staining, immunofluorescence and immunohistochemistry. Additionally, reactive oxygen species (ROS) formation was evaluated by dihydroethidium (DHE) staining; mitochondrial morphology and function were evaluated using transmission electron microscopy and seahorse mitochondrial respiration assay, respectively. The myositis cohort at our centre was subsequently reviewed in terms of cardiac assessments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After the passive transfer of total IgG from patients with positive anti-SRP antibodies, C57BL/6 mice developed significant left ventricular diastolic dysfunction (LVDD). Transcriptomic analysis and corresponding experiments revealed increased oxidative stress and mitochondrial damage in the hearts of the experimental mice. Cardiomyocytes exposed to anti-SRP-specific IgG, however, recovered normal mitochondrial metabolism after treatment with N-acetylcysteine, an ROS scavenger. Moreover, patients positive for anti-SRP antibodies manifested worse diastolic but equivalent systolic function compared to their counterparts after propensity score matching.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Anti-SRP antibodies may play a pathogenic role in the development of LVDD by promoting ROS production and subsequent myocardial mitochondrial impairment. The inhibition of oxidative stress was effective in reversing anti-SRP antibody-induced LVDD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 8","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973634","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":"Primary SARS-CoV-2 infection in children and adults results in similar Fc-mediated antibody effector function patterns","authors":"Anne T Gelderloos,&nbsp;Anke J Lakerveld,&nbsp;Rutger M Schepp,&nbsp;Mioara Alina Nicolaie,&nbsp;Josine van Beek,&nbsp;Lisa Beckers,&nbsp;Robert S van Binnendijk,&nbsp;Nynke Y Rots,&nbsp;Puck B van Kasteren","doi":"10.1002/cti2.1521","DOIUrl":"10.1002/cti2.1521","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Increasing evidence suggests that Fc-mediated antibody effector functions have an important role in protection against respiratory viruses, including SARS-CoV-2. However, limited data are available on the potential differences in the development, heterogeneity and durability of these responses in children compared to adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we assessed the development of spike S1-specific serum antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD) and natural killer cell activation (ADNKA), alongside specific antibody binding concentrations (IgG, IgA and IgM) and IgG avidity in healthy adults (<i>n</i> = 38, 18–56 years) and children (<i>n</i> = 21, 5–16 years) following primary SARS-CoV-2 infection, with a 10-month longitudinal follow-up. Differences between groups were assessed using a nonparametric Kruskal–Wallis test with Dunn's multiple comparisons test.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found similar (functional) antibody responses in children compared to adults, with a tendency for increased durability in children, which was statistically significant for ADCD (<i>P</i> &lt; 0.05). While ADNKA was strongly reduced in both adults (<i>P</i> &lt; 0.001) and children (<i>P</i> &lt; 0.05) at the latest time point, ADCP remained relatively stable over time, possibly relating to an increase in avidity of the spike-specific antibodies (<i>P</i> &lt; 0.001). Finally, the ADNKA capacity relative to antibody concentration appeared to decrease over time in both children and adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In conclusion, our data provide novel insights into the development of SARS-CoV-2-specific antibody Fc-mediated effector functions in children and adults. An increased understanding of these characteristics in specific age populations is valuable for the future design of novel and improved vaccination strategies for respiratory viruses such as SARS-CoV-2.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 8","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1521","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141770598","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":"Serological responses and clinical outcomes following a three-dose primary COVID-19 vaccine schedule in kidney transplant recipients and people on dialysis","authors":"Dhakshayini Tharmaraj,&nbsp;Irene Boo,&nbsp;Jessie O'Hara,&nbsp;Shir Sun,&nbsp;Kevan R Polkinghorne,&nbsp;Claire Dendle,&nbsp;Stephen J Turner,&nbsp;Menno C van Zelm,&nbsp;Heidi E Drummer,&nbsp;Gabriela Khoury,&nbsp;William R Mulley","doi":"10.1002/cti2.1523","DOIUrl":"10.1002/cti2.1523","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite vaccination strategies, people with chronic kidney disease, particularly kidney transplant recipients (KTRs), remained at high risk of poor COVID-19 outcomes. We assessed serological responses to the three-dose COVID-19 vaccine schedule in KTRs and people on dialysis, as well as seroresponse predictors and the relationship between responses and breakthrough infection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Plasma from 30 KTRs and 17 people receiving dialysis was tested for anti-Spike receptor binding domain (RBD) IgG and neutralising antibodies (NAb) to the ancestral and Omicron BA.2 variant after Doses 2 and 3 of vaccination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After three doses, KTRs achieved lower anti-Spike RBD IgG levels (<i>P</i> &lt; 0.001) and NAb titres than people receiving dialysis (<i>P</i> = 0.002). Seropositive cross-reactive Omicron neutralisation levels were achieved in 11/27 (40.7%) KTRs and 11/14 (78.6%) dialysis recipients. ChAdOx1/viral-vector vaccine type, higher mycophenolate dose (&gt; 1 g per day) and lower absolute B-cell counts predicted poor serological responses in KTRs. ChAdOx-1 vaccine type and higher monocyte counts were negative predictors in dialysis recipients. Among ancestral NAb seroresponders, higher NAb levels positively correlated with higher Omicron neutralisation (<i>R</i> = 0.9, <i>P</i> &lt; 0.001). More KTRs contracted SARS-CoV-2 infection (14/30; 47%) than dialysis recipients (5/17; 29%) and had more severe disease. Those with breakthrough infections had significantly lower median interdose incremental change in anti-Spike RBD IgG and ancestral NAb titres.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Serological responses to COVID-19 vaccines in KTRs lag behind their dialysis counterparts. KTRs remained at high risk of breakthrough infection after their primary vaccination schedule underlining their need for booster doses, strict infection prevention measures and close surveillance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11272417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755898","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":"Spatial proteomic profiling of tumor and stromal compartments in non-small-cell lung cancer identifies signatures associated with overall survival","authors":"Vahid Yaghoubi Naei,&nbsp;James Monkman,&nbsp;Habib Sadeghirad,&nbsp;Ahmed Mehdi,&nbsp;Tony Blick,&nbsp;William Mullally,&nbsp;Ken O'Byrne,&nbsp;Majid Ebrahimi Warkiani,&nbsp;Arutha Kulasinghe","doi":"10.1002/cti2.1522","DOIUrl":"10.1002/cti2.1522","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Non-small-cell lung carcinoma (NSCLC) is the most prevalent and lethal form of lung cancer. The need for biomarker-informed stratification of targeted therapies has underpinned the need to uncover the underlying properties of the tumor microenvironment (TME) through high-plex quantitative assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we profiled resected NSCLC tissues from 102 patients by targeted spatial proteomics of 78 proteins across tumor, immune activation, immune cell typing, immune-oncology, drug targets, cell death and PI3K/AKT modules to identify the tumor and stromal signatures associated with overall survival (OS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Survival analysis revealed that stromal CD56 (HR = 0.384, <i>P</i> = 0.06) and tumoral TIM3 (HR = 0.703, <i>P</i> = 0.05) were associated with better survival in univariate Cox models. In contrast, after adjusting for stage, BCLXL (HR = 2.093, <i>P</i> = 0.02) and cleaved caspase 9 (HR = 1.575, <i>P</i> = 0.1) negatively influenced survival. Delta testing indicated the protective effect of TIM-3 (HR = 0.614, <i>P</i> = 0.04) on OS. In multivariate analysis, CD56 (HR = 0.172, <i>P</i> = 0.001) was associated with better survival in the stroma, while B7.H3 (HR = 1.72, <i>P</i> = 0.008) was linked to poorer survival in the tumor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Deciphering the TME using high-plex spatially resolved methods is giving us new insights into compartmentalised tumor and stromal protein signatures associated with clinical endpoints in NSCLC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722755","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":"Endogenous bystander killing mechanisms enhance the activity of novel FAP-specific CAR-T cells against glioblastoma","authors":"Wenbo Yu,&nbsp;Nga TH Truong,&nbsp;Ruhi Polara,&nbsp;Tessa Gargett,&nbsp;Melinda N Tea,&nbsp;Stuart M Pitson,&nbsp;Michaelia P Cockshell,&nbsp;Claudine S Bonder,&nbsp;Lisa M Ebert,&nbsp;Michael P Brown","doi":"10.1002/cti2.1519","DOIUrl":"https://doi.org/10.1002/cti2.1519","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>CAR-T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR-T cells targeting FAP have never been investigated as a therapy for glioblastoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR-T cells for their lytic activity and cytokine secretion function <i>in vitro</i> (using real-time impedance, flow cytometry, imaging and bead-based cytokine assays), and <i>in vivo</i> (using a xenograft mimicking the natural heterogeneity of human glioblastoma).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>FAP-CAR-T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient-derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co-culture assays, we confirmed FAP-CAR-T cells mediate bystander killing of antigen-negative tumor cells, but only after activation by FAP-positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL-2 which activated the non-transduced fraction of the CAR-T product. Finally, a low dose of intravenously administered FAP-CAR-T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen-negative and antigen-positive glioblastoma cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings advance FAP as a leading candidate for clinical CAR-T therapy of glioblastoma and highlight under-recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR-T cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537018","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":"Metabolic requirements of CD160 expressing memory-like NK cells in Gram-negative bacterial infection","authors":"Anucha Preechanukul,&nbsp;Natnaree Saiprom,&nbsp;Kitilak Rochaikun,&nbsp;Boonthanom Moonmueangsan,&nbsp;Rungnapa Phunpang,&nbsp;Orawan Ottiwet,&nbsp;Yuphin Kongphrai,&nbsp;Soonthon Wapee,&nbsp;Rachan Janon,&nbsp;Susanna Dunachie,&nbsp;Barbara Kronsteiner,&nbsp;Narisara Chantratita","doi":"10.1002/cti2.1513","DOIUrl":"10.1002/cti2.1513","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Unique metabolic requirements accompany the development and functional fates of immune cells. How cellular metabolism is important in natural killer (NK) cells and their memory-like differentiation in bacterial infections remains elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we utilise our established NK cell memory assay to investigate the metabolic requirement for memory-like NK cell formation and function in response to the Gram-negative intracellular bacteria <i>Burkholderia pseudomallei</i> (BP), the causative agent of melioidosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrate that CD160⁺ memory-like NK cells upon BP stimulation upregulate glucose and amino acid transporters in a cohort of recovered melioidosis patients which is maintained at least 3-month post-hospital admission. Using an <i>in vitro</i> assay, human BP-specific CD160⁺ memory-like NK cells show metabolic priming including increased expression of glucose and amino acid transporters with elevated glucose uptake, increased mTOR activation and mitochondrial membrane potential upon BP re-stimulation. Antigen-specific and cytokine-induced IFN-γ production of this memory-like NK cell subset are highly dependent on oxidative phosphorylation (OXPHOS) with some dependency on glycolysis, whereas the formation of CD160⁺ memory-like NK cells <i>in vitro</i> is dependent on fatty acid oxidation and OXPHOS and further increased by metformin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study reveals the link between metabolism and cellular function of memory-like NK cells, which can be exploited for vaccine design and for monitoring protection against Gram-negative bacterial infection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490219","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}