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.
Methods
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 Burkholderia pseudomallei (BP), the causative agent of melioidosis.
Results
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 in vitro 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 in vitro is dependent on fatty acid oxidation and OXPHOS and further increased by metformin.
Conclusion
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.
目的：免疫细胞的发育和功能命运伴随着独特的代谢要求。方法：在此，我们利用已建立的 NK 细胞记忆试验来研究记忆样 NK 细胞形成和功能对革兰氏阴性细胞内细菌假丝状伯克霍尔德氏菌（Burkholderia pseudomallei，BP）（美拉菌病的致病菌）的代谢要求：结果：我们证明，在一组已康复的类鼻疽患者中，CD160+记忆样NK细胞在受到BP刺激后会上调葡萄糖和氨基酸转运体，这种情况在入院后至少维持了3个月。通过体外试验，人类 BP 特异性 CD160+ 记忆样 NK 细胞在 BP 再刺激时表现出新陈代谢启动，包括葡萄糖和氨基酸转运体表达增加，葡萄糖摄取量升高，mTOR 激活和线粒体膜电位升高。这种记忆样 NK 细胞亚群的抗原特异性和细胞因子诱导的 IFN-γ 生成高度依赖于氧化磷酸化（OXPHOS），并在一定程度上依赖于糖酵解，而体外 CD160+ 记忆样 NK 细胞的形成依赖于脂肪酸氧化和 OXPHOS，二甲双胍可进一步提高其生成：这项研究揭示了记忆样 NK 细胞的代谢与细胞功能之间的联系，可用于疫苗设计和监测对革兰氏阴性细菌感染的保护。
{"title":"Metabolic requirements of CD160 expressing memory-like NK cells in Gram-negative bacterial infection","authors":"Anucha Preechanukul, Natnaree Saiprom, Kitilak Rochaikun, Boonthanom Moonmueangsan, Rungnapa Phunpang, Orawan Ottiwet, Yuphin Kongphrai, Soonthon Wapee, Rachan Janon, Susanna Dunachie, Barbara Kronsteiner, 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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":null,"pages":null},"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}
Han Shuwen, Song Yifei, Wu Xinyue, Qu Zhanbo, Yu Xiang, Yang Xi
In recent years, bacteria have gained considerable attention as a promising drug carrier that is critical in improving the effectiveness and reducing the side effects of anti-tumor drugs. Drug carriers can be utilised in various forms, including magnetotactic bacteria, bacterial biohybrids, minicells, bacterial ghosts and bacterial spores. Additionally, functionalised and engineered bacteria obtained through gene engineering and surface modification could provide enhanced capabilities for drug delivery. This review summarises the current studies on bacteria-based drug delivery systems for anti-tumor therapy and discusses the prospects and challenges of bacteria as drug carriers. Furthermore, our findings aim to provide new directions and guidance for the research on bacteria-based drug systems.
{"title":"Advances in bacteria-based drug delivery systems for anti-tumor therapy","authors":"Han Shuwen, Song Yifei, Wu Xinyue, Qu Zhanbo, Yu Xiang, Yang Xi","doi":"10.1002/cti2.1518","DOIUrl":"10.1002/cti2.1518","url":null,"abstract":"<p>In recent years, bacteria have gained considerable attention as a promising drug carrier that is critical in improving the effectiveness and reducing the side effects of anti-tumor drugs. Drug carriers can be utilised in various forms, including magnetotactic bacteria, bacterial biohybrids, minicells, bacterial ghosts and bacterial spores. Additionally, functionalised and engineered bacteria obtained through gene engineering and surface modification could provide enhanced capabilities for drug delivery. This review summarises the current studies on bacteria-based drug delivery systems for anti-tumor therapy and discusses the prospects and challenges of bacteria as drug carriers. Furthermore, our findings aim to provide new directions and guidance for the research on bacteria-based drug systems.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464616","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}
Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are poorly informative about interferon (IFN)-related disorders. In these conditions, the measure of the interferon score (IS), obtained by measuring the expression of IFN-stimulated genes, has been proposed. Flow cytometry-based assays measuring sialic-acid-binding Ig-like lectin 1 (Siglec-1) expression could be a more practical tool for evaluating IFN-inflammation. The study compared Siglec-1 measures with IS and other inflammatory indexes. We compared Siglec-1 measures with IS and other inflammatory indexes in real-world paediatric rheumatology experience.
Methods
We recruited patients with immuno-rheumatological conditions, acute infectious illness and patients undergoing orthopaedic surgery as controls. Siglec-1 expression was measured in all samples, and IS, ESR and CRP were also recorded if available.
Results
Overall, 98 subjects were enrolled in the study, with a total of 104 measures of Siglec-1. Compared with IS, Siglec-1 expression showed good accuracy (86.0%), specificity (72.7%) and sensitivity (85.7%). The measure of the percentage of Siglec-1-positive cells performed best at low levels of IFN-inflammation, while the measure of mean fluorescence intensity performed best at higher levels. Ex vivo studies on IFN-stimulated monocytes confirmed this behaviour. There was no link between Siglec-1 expression and either ESR or CRP, and positive Siglec-1 results were found even when ESR and CRP were normal. A high Siglec-1 expression was also recorded in subjects with acute infections.
Conclusion
Siglec-1 measurement by flow cytometry is an easy tool to detect IFN-related inflammation, even in subjects with normal results of common inflammation indexes.
{"title":"Siglec-1, an easy and contributory inflammation marker in rheumatology","authors":"Valentina Boz, Alessandra Tesser, Francesca Burlo, Nicola Donadel, Serena Pastore, Alessandro Amaddeo, Francesca Vittoria, Matteo Padovan, Marianna Di Rosa, Alberto Tommasini, Erica Valencic","doi":"10.1002/cti2.1520","DOIUrl":"10.1002/cti2.1520","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are poorly informative about interferon (IFN)-related disorders. In these conditions, the measure of the interferon score (IS), obtained by measuring the expression of IFN-stimulated genes, has been proposed. Flow cytometry-based assays measuring sialic-acid-binding Ig-like lectin 1 (Siglec-1) expression could be a more practical tool for evaluating IFN-inflammation. The study compared Siglec-1 measures with IS and other inflammatory indexes. We compared Siglec-1 measures with IS and other inflammatory indexes in real-world paediatric rheumatology experience.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We recruited patients with immuno-rheumatological conditions, acute infectious illness and patients undergoing orthopaedic surgery as controls. Siglec-1 expression was measured in all samples, and IS, ESR and CRP were also recorded if available.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 98 subjects were enrolled in the study, with a total of 104 measures of Siglec-1. Compared with IS, Siglec-1 expression showed good accuracy (86.0%), specificity (72.7%) and sensitivity (85.7%). The measure of the percentage of Siglec-1-positive cells performed best at low levels of IFN-inflammation, while the measure of mean fluorescence intensity performed best at higher levels. <i>Ex vivo</i> studies on IFN-stimulated monocytes confirmed this behaviour. There was no link between Siglec-1 expression and either ESR or CRP, and positive Siglec-1 results were found even when ESR and CRP were normal. A high Siglec-1 expression was also recorded in subjects with acute infections.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Siglec-1 measurement by flow cytometry is an easy tool to detect IFN-related inflammation, even in subjects with normal results of common inflammation indexes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464617","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}
Lindsay E Clegg, Oleg Stepanov, Sam Matthews, Tom White, Seth Seegobin, Steven Thomas, Kevin M Tuffy, Mats Någård, Mark T Esser, Katie Streicher, Taylor S Cohen, Anastasia A Aksyuk
Objectives
The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.g. storing infectious viruses and testing at biosafety level-3 facilities). Here, we demonstrate the utility of pseudovirus neutralisation assay data in conjunction with serum mAb concentrations to robustly predict nAb titres in serum.
Methods
SARS-CoV-2 nAb titres were determined via authentic- and lentiviral pseudovirus-based neutralisation assays using serological data from three AZD7442 (tixagevimab–cilgavimab) studies: PROVENT (NCT04625725), TACKLE (NCT04723394) and a phase 1 dose-ranging study (NCT04507256). AZD7442 serum concentrations were assessed using immunocapture. Serum-based half-maximal inhibitory concentration (IC50) values were derived from pseudovirus nAb titres and serum mAb concentrations, and compared with in vitro IC50 measurements.
Results
nAb titres measured via authentic- and lentiviral pseudovirus-based neutralisation assays were strongly correlated for the ancestral SARS-CoV-2 virus and SARS-CoV-2 Alpha. Serum AZD7442 concentrations and pseudovirus nAb titres were strongly correlated for multiple SARS-CoV-2 variants with all Spearman correlation coefficients ≥ 0.78. Serum-based IC50 values were similar to in vitro IC50 values for AZD7442, for ancestral SARS-CoV-2 and Alpha, Delta, Omicron BA.2 and Omicron BA.4/5 variants.
Conclusions
These data highlight that serum mAb concentrations and pseudovirus in vitro IC50 values can be used to rapidly predict nAb titres in serum for emerging and historical SARS-CoV-2 variants.
{"title":"Serum AZD7442 (tixagevimab–cilgavimab) concentrations and in vitro IC50 values predict SARS-CoV-2 neutralising antibody titres","authors":"Lindsay E Clegg, Oleg Stepanov, Sam Matthews, Tom White, Seth Seegobin, Steven Thomas, Kevin M Tuffy, Mats Någård, Mark T Esser, Katie Streicher, Taylor S Cohen, Anastasia A Aksyuk","doi":"10.1002/cti2.1517","DOIUrl":"10.1002/cti2.1517","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.g. storing infectious viruses and testing at biosafety level-3 facilities). Here, we demonstrate the utility of pseudovirus neutralisation assay data in conjunction with serum mAb concentrations to robustly predict nAb titres in serum.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SARS-CoV-2 nAb titres were determined via authentic- and lentiviral pseudovirus-based neutralisation assays using serological data from three AZD7442 (tixagevimab–cilgavimab) studies: PROVENT (NCT04625725), TACKLE (NCT04723394) and a phase 1 dose-ranging study (NCT04507256). AZD7442 serum concentrations were assessed using immunocapture. Serum-based half-maximal inhibitory concentration (IC<sub>50</sub>) values were derived from pseudovirus nAb titres and serum mAb concentrations, and compared with <i>in vitro</i> IC<sub>50</sub> measurements.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>nAb titres measured via authentic- and lentiviral pseudovirus-based neutralisation assays were strongly correlated for the ancestral SARS-CoV-2 virus and SARS-CoV-2 Alpha. Serum AZD7442 concentrations and pseudovirus nAb titres were strongly correlated for multiple SARS-CoV-2 variants with all Spearman correlation coefficients ≥ 0.78. Serum-based IC<sub>50</sub> values were similar to <i>in vitro</i> IC<sub>50</sub> values for AZD7442, for ancestral SARS-CoV-2 and Alpha, Delta, Omicron BA.2 and Omicron BA.4/5 variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These data highlight that serum mAb concentrations and pseudovirus <i>in vitro</i> IC<sub>50</sub> values can be used to rapidly predict nAb titres in serum for emerging and historical SARS-CoV-2 variants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11175839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316242","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}
Wytske J Fokkens, Claus Bachert, Claire Hopkins, Osama Marglani, Amy Praestgaard, Scott Nash, Yamo Deniz, Paul J Rowe, Harry Sacks, Juby A Jacob-Nara
Objectives
This post hoc analysis assessed disease characteristics and response to dupilumab treatment in male and female patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (SINUS-52 study; NCT02898454).
Methods
Patients received dupilumab 300 mg or placebo every 2 weeks for 52 weeks on background intranasal corticosteroids. Efficacy was assessed through Week 52 using nasal polyp score (NPS), nasal congestion/obstruction score, loss of smell score and University of Pennsylvania Smell Identification Test score. Disease-specific health-related quality of life (HRQoL) was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22).
Results
The analysis included 192 male and 111 female patients. Female patients had higher mean SNOT-22 total score (56.6 vs. 49.1, P < 0.01) and more coexisting asthma (78.4% vs. 46.4%, P < 0.0001) and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) (38.7% vs. 18.8%, P = 0.0001) than male patients, but other baseline characteristics were similar. Dupilumab significantly improved CRSwNP outcomes vs. placebo at Week 52, regardless of gender: least squares mean differences (95% confidence interval) for NPS were −2.33 (−2.80, −1.86) in male and −2.54 (−3.18, −1.90) in female patients (both P < 0.0001 vs. placebo), and for SNOT-22 were −19.2 (−24.1, −14.2) in male and −24.4 (−31.5, −17.3) in female patients (both P < 0.0001 vs. placebo). There were no significant efficacy-by-gender interactions.
Conclusion
Female patients had greater asthma, NSAID-ERD and HRQoL burden at baseline than male patients. Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender.
{"title":"Dupilumab improves outcomes in patients with chronic rhinosinusitis with nasal polyps irrespective of gender: results from the SINUS-52 trial","authors":"Wytske J Fokkens, Claus Bachert, Claire Hopkins, Osama Marglani, Amy Praestgaard, Scott Nash, Yamo Deniz, Paul J Rowe, Harry Sacks, Juby A Jacob-Nara","doi":"10.1002/cti2.1511","DOIUrl":"https://doi.org/10.1002/cti2.1511","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This <i>post hoc</i> analysis assessed disease characteristics and response to dupilumab treatment in male and female patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (SINUS-52 study; NCT02898454).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients received dupilumab 300 mg or placebo every 2 weeks for 52 weeks on background intranasal corticosteroids. Efficacy was assessed through Week 52 using nasal polyp score (NPS), nasal congestion/obstruction score, loss of smell score and University of Pennsylvania Smell Identification Test score. Disease-specific health-related quality of life (HRQoL) was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The analysis included 192 male and 111 female patients. Female patients had higher mean SNOT-22 total score (56.6 vs. 49.1, <i>P</i> < 0.01) and more coexisting asthma (78.4% vs. 46.4%, <i>P</i> < 0.0001) and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) (38.7% vs. 18.8%, <i>P</i> = 0.0001) than male patients, but other baseline characteristics were similar. Dupilumab significantly improved CRSwNP outcomes vs. placebo at Week 52, regardless of gender: least squares mean differences (95% confidence interval) for NPS were −2.33 (−2.80, −1.86) in male and −2.54 (−3.18, −1.90) in female patients (both <i>P</i> < 0.0001 vs. placebo), and for SNOT-22 were −19.2 (−24.1, −14.2) in male and −24.4 (−31.5, −17.3) in female patients (both <i>P</i> < 0.0001 vs. placebo). There were no significant efficacy-by-gender interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Female patients had greater asthma, NSAID-ERD and HRQoL burden at baseline than male patients. Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141292571","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}
Vahid Yaghoubi Naei, Ekaterina Ivanova, William Mullally, Connor G O'Leary, Rahul Ladwa, Ken O'Byrne, Majid E Warkiani, Arutha Kulasinghe
Objectives
Globally, non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and the leading cause of cancer-related deaths. Tumor-associated circulating cells in NSCLC can have a wide variety of morphological and phenotypic characteristics, including epithelial, immunological or hybrid subtypes. The distinctive characteristics and potential clinical significance of these cells in patients with NSCLC are explored in this study.
Methods
We utilised a spiral microfluidic device to enrich large cells and cell aggregates from the peripheral blood samples of NSCLC patients. These cells were characterised through high-resolution immunofluorescent imaging and statistical analysis, correlating findings with clinical information from our patient cohort.
Results
We have identified varied populations of heterotypic circulating tumor cell clusters with differing immune cell composition that included a distinct class of atypical tumor-associated macrophages that exhibits unique morphology and cell size. This subtype's prevalence is positively correlated with the tumor stage, progression and metastasis.
Conclusions
Our study reveals a heterogeneous landscape of circulating tumor cells and their clusters, underscoring the complexity of NSCLC pathobiology. The identification of a unique subtype of atypical tumor-associatedmacrophages that simultaneously express both tumor and immune markers and whose presence correlates with late disease stages, poor clinical outcomes and metastatic risk infers the potential of these cells as biomarkers for NSCLC staging and prognosis. Future studies should focus on the role of these cells in the tumor microenvironment and their potential as therapeutic targets. Additionally, longitudinal studies tracking these cell types through disease progression could provide further insights into their roles in NSCLC evolution and response to treatment.
{"title":"Characterisation of circulating tumor-associated and immune cells in patients with advanced-stage non-small cell lung cancer","authors":"Vahid Yaghoubi Naei, Ekaterina Ivanova, William Mullally, Connor G O'Leary, Rahul Ladwa, Ken O'Byrne, Majid E Warkiani, Arutha Kulasinghe","doi":"10.1002/cti2.1516","DOIUrl":"https://doi.org/10.1002/cti2.1516","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Globally, non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and the leading cause of cancer-related deaths. Tumor-associated circulating cells in NSCLC can have a wide variety of morphological and phenotypic characteristics, including epithelial, immunological or hybrid subtypes. The distinctive characteristics and potential clinical significance of these cells in patients with NSCLC are explored in this study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We utilised a spiral microfluidic device to enrich large cells and cell aggregates from the peripheral blood samples of NSCLC patients. These cells were characterised through high-resolution immunofluorescent imaging and statistical analysis, correlating findings with clinical information from our patient cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We have identified varied populations of heterotypic circulating tumor cell clusters with differing immune cell composition that included a distinct class of atypical tumor-associated macrophages that exhibits unique morphology and cell size. This subtype's prevalence is positively correlated with the tumor stage, progression and metastasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study reveals a heterogeneous landscape of circulating tumor cells and their clusters, underscoring the complexity of NSCLC pathobiology. The identification of a unique subtype of atypical tumor-associatedmacrophages that simultaneously express both tumor and immune markers and whose presence correlates with late disease stages, poor clinical outcomes and metastatic risk infers the potential of these cells as biomarkers for NSCLC staging and prognosis. Future studies should focus on the role of these cells in the tumor microenvironment and their potential as therapeutic targets. Additionally, longitudinal studies tracking these cell types through disease progression could provide further insights into their roles in NSCLC evolution and response to treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1516","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245980","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}
Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein–Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation.
Methods
We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction.
Results
Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months.
Conclusions
Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.
{"title":"Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma","authors":"Yu-Min Zhong, Ji Chen, Jie Jiang, Wen-Bin Zhou, Ling-Ling Gao, Shui-Lian Zhang, Wen-Qing Yan, Yu Chen, Dong-Kun Zhang, Dan-Xia Lu, Zhi-Yi Lv, Zhi Xie, Ying Huang, Wei-Bang Guo, Bin-Chao Wang, Jin-Ji Yang, Xue-Ning Yang, Yi-Long Wu, Xu-Chao Zhang","doi":"10.1002/cti2.1515","DOIUrl":"https://doi.org/10.1002/cti2.1515","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein–Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral <i>EBNA-1</i> and <i>BamHI-W</i> DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Progression-free survival (PFS) was significantly longer in <i>EBNA-1</i> high or <i>BamHI-W</i> high groups. A longer PFS was also observed in patients with both high plasma <i>EBNA-1</i> or <i>BamHI-W</i> and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with <i>EBNA-1</i> and <i>BamHI-W</i>. Plasma EBV load was negatively associated with intratumoral CD8<sup>+</sup> immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245979","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}
Veronika Bandara, Victoria M Niktaras, Vasiliki J Willett, Hayley Chapman, Noor A Lokman, Anne M Macpherson, Silvana Napoli, Batjargal Gundsambuu, Jade Foeng, Timothy J Sadlon, Justin Coombs, Shaun R McColl, Simon C Barry, Martin K Oehler, Carmela Ricciardelli
Objectives
Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using in vitro and in vivo models.
Methods
We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites in vitro using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7-CAR-T cells on patient-derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7-CAR-T cells in vivo using the OVCAR-3 xenograft model in NOD-scid IL2Rγnull (NSG) mice.
Results
Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3+ T cells in vitro. However, no significant effects of nfP2X7-CAR-T cells were observed for SKOV3 or normal peritoneal cells (LP-9) cells with low P2X7 receptor expression. Treatment with nfP2X7-CAR-T cells increased apoptosis compared with un-transduced T cells in patient-derived explants and correlated with CD3 positivity. Treatment with nfP2X7-CAR-T cells significantly reduced OVCAR3 tumour burden in mice compared with un-transduced CD3 cells for 7–8 weeks.
Conclusion
This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.
{"title":"Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer","authors":"Veronika Bandara, Victoria M Niktaras, Vasiliki J Willett, Hayley Chapman, Noor A Lokman, Anne M Macpherson, Silvana Napoli, Batjargal Gundsambuu, Jade Foeng, Timothy J Sadlon, Justin Coombs, Shaun R McColl, Simon C Barry, Martin K Oehler, Carmela Ricciardelli","doi":"10.1002/cti2.1512","DOIUrl":"https://doi.org/10.1002/cti2.1512","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using <i>in vitro</i> and <i>in vivo</i> models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites <i>in vitro</i> using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7-CAR-T cells on patient-derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7-CAR-T cells <i>in vivo</i> using the OVCAR-3 xenograft model in NOD-scid IL2Rγnull (NSG) mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3<sup>+</sup> T cells <i>in vitro</i>. However, no significant effects of nfP2X7-CAR-T cells were observed for SKOV3 or normal peritoneal cells (LP-9) cells with low P2X7 receptor expression. Treatment with nfP2X7-CAR-T cells increased apoptosis compared with un-transduced T cells in patient-derived explants and correlated with CD3 positivity. Treatment with nfP2X7-CAR-T cells significantly reduced OVCAR3 tumour burden in mice compared with un-transduced CD3 cells for 7–8 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1512","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141091440","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}
Ge Jin, Runze Wang, Yi Jin, Yingqiu Song, Tianlu Wang
Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected 700 million people worldwide since its outbreak in 2019. The current pandemic strains, including Omicron and its large subvariant series, exhibit strong transmission and stealth. After entering the human body, the virus first infects nasal epithelial cells and invades host cells through the angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 on the host cell surface. The nasal cavity is an important body part that protects against the virus. Immunisation of the nasal mucosa produces immunoglobulin A antibodies that effectively neutralise viruses. Saline nasal irrigation, a type of physical therapy, can reduce the viral load in the nasal cavity and prevent viral infections to some extent. As a commonly used means to fight SARS-CoV-2, the intramuscular (IM) vaccine can induce the human body to produce a systemic immune response and immunoglobulin G antibody; however, the antibody is difficult to distribute to the nasal mucosa in time and cannot achieve a good preventive effect. Intranasal (IN) vaccines compensate for the shortcomings of IM vaccines, induce mucosal immune responses, and have a better effect in preventing infection. In this review, we discuss the nasal defence barrier, the harm caused by SARS-CoV-2, the mechanism of its invasion into host cells, nasal cleaning, IM vaccines and IN vaccines, and suggest increasing the development of IN vaccines, and use of IN vaccines as a supplement to IM vaccines.
由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的冠状病毒病 2019 年自爆发以来已影响全球 7 亿人。目前流行的毒株，包括Omicron及其大型亚变种系列，表现出很强的传播性和隐蔽性。病毒进入人体后，首先感染鼻腔上皮细胞，通过宿主细胞表面的血管紧张素转换酶2受体和跨膜丝氨酸蛋白酶2侵入宿主细胞。鼻腔是人体抵御病毒的重要部位。鼻黏膜免疫可产生免疫球蛋白 A 抗体，有效中和病毒。生理盐水鼻腔冲洗是一种物理疗法，可以减少鼻腔内的病毒载量，在一定程度上预防病毒感染。作为抗击 SARS-CoV-2 的常用手段，肌肉注射（IM）疫苗可诱导人体产生全身免疫反应和免疫球蛋白 G 抗体，但抗体难以及时分布到鼻黏膜，达不到良好的预防效果。鼻内（IN）疫苗弥补了IM疫苗的不足，可诱导粘膜免疫反应，预防感染效果更好。在这篇综述中，我们讨论了鼻腔防御屏障、SARS-CoV-2 的危害、其侵入宿主细胞的机制、鼻腔清洁、IM 疫苗和 IN 疫苗，并建议加大 IN 疫苗的开发力度，将 IN 疫苗作为 IM 疫苗的补充。
{"title":"From intramuscular to nasal: unleashing the potential of nasal spray vaccines against coronavirus disease 2019","authors":"Ge Jin, Runze Wang, Yi Jin, Yingqiu Song, Tianlu Wang","doi":"10.1002/cti2.1514","DOIUrl":"https://doi.org/10.1002/cti2.1514","url":null,"abstract":"<p>Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected 700 million people worldwide since its outbreak in 2019. The current pandemic strains, including Omicron and its large subvariant series, exhibit strong transmission and stealth. After entering the human body, the virus first infects nasal epithelial cells and invades host cells through the angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 on the host cell surface. The nasal cavity is an important body part that protects against the virus. Immunisation of the nasal mucosa produces immunoglobulin A antibodies that effectively neutralise viruses. Saline nasal irrigation, a type of physical therapy, can reduce the viral load in the nasal cavity and prevent viral infections to some extent. As a commonly used means to fight SARS-CoV-2, the intramuscular (IM) vaccine can induce the human body to produce a systemic immune response and immunoglobulin G antibody; however, the antibody is difficult to distribute to the nasal mucosa in time and cannot achieve a good preventive effect. Intranasal (IN) vaccines compensate for the shortcomings of IM vaccines, induce mucosal immune responses, and have a better effect in preventing infection. In this review, we discuss the nasal defence barrier, the harm caused by SARS-CoV-2, the mechanism of its invasion into host cells, nasal cleaning, IM vaccines and IN vaccines, and suggest increasing the development of IN vaccines, and use of IN vaccines as a supplement to IM vaccines.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069092","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}
Samuel Liwei Leong, Lawton Murdolo, Janesha C Maddumage, Marios Koutsakos, Katherine Kedzierska, Anthony W Purcell, Stephanie Gras, Emma J Grant
Objectives
Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8+ T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8+ T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8+ T cell responses across broad populations. Consequently, the rational design of a CD8+ T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules.
Methods
Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule.
Results
Using CD8+ T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01+ individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8+ T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP219 peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides.
Conclusion
Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses.
尽管有疫苗可用，但季节性流感病毒每年仍会导致大约 65 万人死亡。CD8+ T 细胞通常能识别来自内部结构和非结构性流感蛋白的流感衍生肽，是未来疫苗设计的一个有吸引力的途径，因为它们能降低感染不同流感病毒株后的疾病严重程度。CD8+ T 细胞能识别由高度多态的人类白细胞抗原 I 类分子（HLA-I）呈现的肽。每种 HLA-I 变体都有不同的肽结合偏好，这对设计能在广泛人群中引起 CD8+ T 细胞反应的疫苗构成了重大障碍。因此，要合理设计 CD8+ T 细胞介导的疫苗，就必须鉴定出限制于一系列不同 HLA 分子的高免疫原性肽。 方法 在此，我们评估了最近发表的六种新型流感衍生肽的免疫原性，这些肽是通过质谱分析鉴定的，并预测能与流行的 HLA-B*18:01 分子结合。 结果 我们使用 CD8+ T 细胞活化试验和蛋白质生物化学方法表明，3/6 种新型多肽在几个 HLA-B*18:01+ 的个体中具有免疫原性，并证实了它们的 HLA-B*18:01 限制。随后，我们比较了 CD8+ T 细胞对之前发现的高免疫原性 HLA-B*18:01 限制性 NP219 肽的反应。通过 X 射线晶体学，我们首次解析了 HLA-B*18:01 呈现免疫原性流感衍生肽的晶体结构。最后，我们剖析了首个针对 HLA-B*18:01 限制性病原体衍生肽的特异性 TCR 反应谱，确定了针对四种肽中每一种肽的私有和限制性反应谱。 结论 总的来说，这些新型免疫原性多肽的特征描述提供了更多的 HLA-B*18:01 限制性疫苗靶标，这些靶标来自基质蛋白 1，也可能来自流感病毒的非结构蛋白和 RNA 聚合酶催化亚基。
{"title":"Characterisation of novel influenza-derived HLA-B*18:01-restricted epitopes","authors":"Samuel Liwei Leong, Lawton Murdolo, Janesha C Maddumage, Marios Koutsakos, Katherine Kedzierska, Anthony W Purcell, Stephanie Gras, Emma J Grant","doi":"10.1002/cti2.1509","DOIUrl":"https://doi.org/10.1002/cti2.1509","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8<sup>+</sup> T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8<sup>+</sup> T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8<sup>+</sup> T cell responses across broad populations. Consequently, the rational design of a CD8<sup>+</sup> T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Using CD8<sup>+</sup> T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01<sup>+</sup> individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8<sup>+</sup> T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP<sub>219</sub> peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907042","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}
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