Immunotherapy advances最新文献

{"title":"Peripheral T cell lymphopenia in COVID-19: potential mechanisms and impact.","authors":"Sifan Zhang,&nbsp;Becca Asquith,&nbsp;Richard Szydlo,&nbsp;John S Tregoning,&nbsp;Katrina M Pollock","doi":"10.1093/immadv/ltab015","DOIUrl":"https://doi.org/10.1093/immadv/ltab015","url":null,"abstract":"<p><p>Immunopathogenesis involving T lymphocytes, which play a key role in defence against viral infection, could contribute to the spectrum of COVID-19 disease and provide an avenue for treatment. To address this question, a review of clinical observational studies and autopsy data in English and Chinese languages was conducted with a search of registered clinical trials. Peripheral lymphopenia affecting CD4 and CD8 T cells was a striking feature of severe COVID-19 compared with non-severe disease. Autopsy data demonstrated infiltration of T cells into organs, particularly the lung. Seventy-four clinical trials are on-going that could target T cell-related pathogenesis, particularly IL-6 pathways. SARS-CoV-2 infection interrupts T cell circulation in patients with severe COVID-19. This could be due to redistribution of T cells into infected organs, activation induced exhaustion, apoptosis, or pyroptosis. Measuring T cell dynamics during COVID-19 will inform clinical risk-stratification of hospitalised patients and could identify those who would benefit most from treatments that target T cells.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab015"},"PeriodicalIF":0.0,"publicationDate":"2021-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40696407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive immunity and vaccination - iron in the spotlight.","authors":"Alexandra E Preston, Hal Drakesmith, Joe N Frost","doi":"10.1093/immadv/ltab007","DOIUrl":"10.1093/immadv/ltab007","url":null,"abstract":"<p><p>Vaccination programmes are critically important to suppress the burden of infectious diseases, saving countless lives globally, as emphasised by the current COVID-19 pandemic. Effective adaptive immune responses are complex processes subject to multiple influences. Recent genetic, pre-clinical, and clinical studies have converged to show that availability of iron is a key factor regulating the development of T and B cell responses to infection and immunisation. Lymphocytes obtain iron from circulating transferrin. The amount of iron bound to transferrin is dependent on dietary iron availability and is decreased during inflammation via upregulation of the iron-regulatory hormone, hepcidin. As iron deficiency and chronic inflammatory states are both globally prevalent health problems, the potential impact of low iron availability on immune responses is significant. We describe the evidence supporting the importance of iron in immunity, highlight important unknowns, and discuss how therapeutic interventions to modulate iron availability might be implementable in the context of vaccination and infectious disease.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltab007"},"PeriodicalIF":4.1,"publicationDate":"2021-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9149796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between incidental statin use and skeletal myopathies in patients treated with immune checkpoint inhibitors.","authors":"Zsofia D Drobni,&nbsp;Sean P Murphy,&nbsp;Raza M Alvi,&nbsp;Charlotte Lee,&nbsp;Jingyi Gong,&nbsp;Ramya C Mosarla,&nbsp;Paula K Rambarat,&nbsp;Sarah B Hartmann,&nbsp;Hannah K Gilman,&nbsp;Leyre Zubiri,&nbsp;Vineet K Raghu,&nbsp;Ryan J Sullivan,&nbsp;Amna Zafar,&nbsp;Daniel A Zlotoff,&nbsp;Meghan E Sise,&nbsp;Amanda C Guidon,&nbsp;Kerry L Reynolds,&nbsp;Michael Dougan,&nbsp;Tomas G Neilan","doi":"10.1093/immadv/ltab014","DOIUrl":"https://doi.org/10.1093/immadv/ltab014","url":null,"abstract":"<p><strong>Objectives: </strong>Skeletal myopathies are highly morbid, and in rare cases even fatal, immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI). Skeletal myopathies are also a recognized statin-associated side effect. It is unknown whether concurrent use of statins and ICIs increases the risk of skeletal myopathies.</p><p><strong>Methods: </strong>This was a retrospective cohort study of all patients who were treated with an ICI at a single academic institution (Massachusetts General Hospital, Boston, MA, USA). The primary outcome of interest was the development of a skeletal myopathy. The secondary outcome of interest was an elevated creatine kinase level (above the upper limit of normal).</p><p><strong>Results: </strong>Among 2757 patients, 861 (31.2%) were treated with a statin at the time of ICI start. Statin users were older, more likely to be male and had a higher prevalence of cardiovascular and non-cardiovascular co-morbidities. During a median follow-up of 194 days (inter quartile range 65-410), a skeletal myopathy occurred in 33 patients (1.2%) and was more common among statin users (2.7 vs. 0.9%, <i>P</i> < 0.001). Creatine kinase (CK) elevation was present in 16.3% (114/699) and was higher among statin users (20.0 vs. 14.3%, <i>P</i> = 0.067). In a multivariable Cox model, statin therapy was associated with a >2-fold higher risk for skeletal myopathy (HR, 2.19; 95% confidence interval, 1.07-4.50; <i>P</i> = 0.033).</p><p><strong>Conclusion: </strong>In this large cohort of ICI-treated patients, a higher risk was observed for skeletal myopathies and elevation in CK levels in patients undergoing concurrent statin therapy. Prospective observational studies are warranted to further elucidate the potential association between statin use and ICI-associated myopathies.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab014"},"PeriodicalIF":0.0,"publicationDate":"2021-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ee/b6/ltab014.PMC8444991.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39453027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α2-3 Sialic acid binding and uptake by human monocyte-derived dendritic cells alters metabolism and cytokine release and initiates tolerizing T cell programming.","authors":"Joyce Lübbers,&nbsp;Rui-Jún Eveline Li,&nbsp;Friederike S Gorki,&nbsp;Sven C M Bruijns,&nbsp;Ashley Gallagher,&nbsp;Hakan Kalay,&nbsp;Martino Ambrosini,&nbsp;Douwe Molenaar,&nbsp;Jan Van den Bossche,&nbsp;Sandra J van Vliet,&nbsp;Yvette van Kooyk","doi":"10.1093/immadv/ltab012","DOIUrl":"https://doi.org/10.1093/immadv/ltab012","url":null,"abstract":"<p><p>Dendritic cells (DCs) are key in the initiation of the adaptive T cell responses to tailor adequate immunity that corresponds to the type of pathogen encountered. Oppositely, DCs control the resolution phase of inflammation and are able to induce tolerance after receiving anti-inflammatory cytokines or upon encounter of self-associated molecular patterns, such as α2-3 linked sialic acid (α2-3sia).</p><p><strong>Objective: </strong>We here investigated whether α2-3sia, that bind immune inhibitory Siglec receptors, would alter signaling and reprogramming of LPS-stimulated human monocyte-derived DCs (moDCs).</p><p><strong>Methods and results: </strong>Transcriptomic analysis of moDCs stimulated with α2-3sia-conjugated dendrimers revealed differentially expressed genes related to metabolic pathways, cytokines, and T cell differentiation. An increase in genes involved in ATPase regulator activity, oxidoreductase activity, and glycogen metabolic processes was detected. Metabolic extracellular flux analysis confirmed a more energetic moDC phenotype upon α2-3sia binding as evidenced by an increase in both glycolysis and mitochondrial oxidative phosphorylation. T_H1 differentiation promoting genes <i>IFNL</i> and <i>IL27</i>, were significantly downregulated in the presence of α2-3sia. Functional assays confirmed that α2-3sia binding to moDCs induced phosphorylation of Siglec-9, reduced production of inflammatory cytokines IL-12 and IL-6, and increased IL-10. Surprisingly, α2-3sia-differentiated moDCs promoted FoxP3⁺CD25^+/-CD127^- regulatory T cell differentiation and decreased FoxP3^-CD25^-CD127^- effector T cell proliferation.</p><p><strong>Conclusions: </strong>In conclusion, we demonstrate that α2-3sia binding to moDCs, phosphorylates Siglec-9, alters metabolic pathways, cytokine signaling, and T cell differentiation processes in moDCs and promotes regulatory T cells. The sialic acid-Siglec axis on DCs is therefore, a novel target to induce tolerance and to explore for immunotherapeutic interventions aimed to restore inflammatory processes.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab012"},"PeriodicalIF":0.0,"publicationDate":"2021-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40596071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behind the scenes with basophils: an emerging therapeutic target.","authors":"Hemali Shah,&nbsp;Stephanie Eisenbarth,&nbsp;Christopher A Tormey,&nbsp;Alexa J Siddon","doi":"10.1093/immadv/ltab008","DOIUrl":"https://doi.org/10.1093/immadv/ltab008","url":null,"abstract":"<p><p>Though basophils were originally viewed as redundant blood 'mast cells', the implementation of flow cytometry has established basophils as unique leukocytes with critical immunomodulatory functions. Basophils play an active role in allergic inflammation, autoimmunity, and hematological malignancies. They are distinguishable from other leukocytes by their characteristic metachromatic deep-purple cytoplasmic, round granules. Mature basophils are phenotypically characterized by surface expression of IL-3Rα (CD123); IL-3 drives basophil differentiation, degranulation, and synthesis of inflammatory mediators including type 2 cytokines. Basophil degranulation is the predominant source of histamine in peripheral blood, promoting allergic responses. Basophils serve as a bridge between innate and adaptive immunity by secreting IL-4 which supports eosinophil migration, monocyte differentiation into macrophages, B-cell activation, and CD4 T-cell differentiation into Th2 cells. Further, basophilia is a key phenomenon in myeloid neoplasms, especially chronic myeloid leukemia (CML) for which it is a diagnostic criterion. Increased circulating basophils, often with aberrant immunophenotype, have been detected in patients with CML and other myeloproliferative neoplasms (MPNs). The significance of basophils' immunoregulatory functions in malignant and non-malignant diseases is an active area of research. Ongoing and future research can inform the development of immunotherapies that target basophils to impact allergic, autoimmune, and malignant disease states. This review article aims to provide an overview of basophil biology, identification strategies, and roles and dysregulation in diseases.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab008"},"PeriodicalIF":0.0,"publicationDate":"2021-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/09/6d/ltab008.PMC9327101.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40596070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs: immune modulators in cancer immunotherapy.","authors":"Yun Xing,&nbsp;Zhiqiang Wang,&nbsp;Zhou Lu,&nbsp;Jie Xia,&nbsp;Zhangjuan Xie,&nbsp;Mengxia Jiao,&nbsp;Ronghua Liu,&nbsp;Yiwei Chu","doi":"10.1093/immadv/ltab006","DOIUrl":"https://doi.org/10.1093/immadv/ltab006","url":null,"abstract":"<p><p>MicroRNA (miRNA) is a class of endogenous small non-coding RNA of 18-25 nucleotides and plays regulatory roles in both physiological and pathological processes. Emerging evidence support that miRNAs function as immune modulators in tumors. MiRNAs as tumor suppressors or oncogenes are also found to be able to modulate anti-tumor immunity or link the crosstalk between tumor cells and immune cells surrounding. Based on the specific regulating function, miRNAs can be used as predictive, prognostic biomarkers, and therapeutic targets in immunotherapy. Here, we review new findings about the role of miRNAs in modulating immune responses, as well as discuss mechanisms underlying their dysregulation, and their clinical potentials as indicators of tumor prognosis or to sensitize cancer immunotherapy.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab006"},"PeriodicalIF":0.0,"publicationDate":"2021-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltab006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40596068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells.","authors":"Matthias Eberl, Eric Oldfield, Thomas Herrmann","doi":"10.1093/immadv/ltab005","DOIUrl":"10.1093/immadv/ltab005","url":null,"abstract":"<p><p>Human Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells, and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T cells of compounds like (<i>E</i>)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), the penultimate metabolite in the MEP isoprenoid biosynthesis pathway, and intermediates of the riboflavin biosynthesis pathway and their metabolites allows the immune system to rapidly sense pathogen-associated molecular patterns that are shared by a wide range of micro-organisms. Given the essential nature of these metabolic pathways for microbial viability, they have emerged as promising targets for the development of novel antibiotics. Here, we review recent findings that link enzymatic inhibition of microbial metabolism with alterations in the levels of unconventional T cell ligands produced by treated micro-organisms that have given rise to the concept of 'immuno-antibiotics': combining direct antimicrobial activity with an immunotherapeutic effect via modulation of unconventional T cell responses.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltab005"},"PeriodicalIF":4.1,"publicationDate":"2021-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10334639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An overview of CAR T-cell clinical trial activity to 2021.","authors":"Antonella Adami, John Maher","doi":"10.1093/immadv/ltab004","DOIUrl":"10.1093/immadv/ltab004","url":null,"abstract":"<p><p>Immunotherapy of cancer using chimeric antigen receptor-engineered T-cells has transformed the management of selected haematological malignancies, triggering intense clinical trial activity in this arena. This article summarises trial activity that has been published to date across the spectrum of haematological and solid tumour types.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab004"},"PeriodicalIF":4.1,"publicationDate":"2021-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38954775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF1R defines the mononuclear phagocyte system lineage in human blood in health and COVID-19.","authors":"Theo W Combes, Federica Orsenigo, Alexander Stewart, A S Jeewaka R Mendis, Deborah Dunn-Walters, Siamon Gordon, Fernando O Martinez","doi":"10.1093/immadv/ltab003","DOIUrl":"10.1093/immadv/ltab003","url":null,"abstract":"<p><p>Mononuclear phagocytes defend tissues, present antigens, and mediate recovery and healing. To date, we lack a marker to unify mononuclear phagocytes in humans or that informs us about their origin. Here, we reassess mononuclear phagocyte ontogeny in human blood through the lineage receptor CSF1R, in the steady state and in COVID-19. We define CSF1R as the first sensitive and reproducible pan-phagocyte lineage marker, to identify and enumerate all conventional monocytes, and the myeloid dendritic cells. In the steady state, CSF1R is sufficient for sorting and immuno-magnetic isolation. In pathology, changes in CSF1R are more sensitive than CD14 and CD16. In COVID-19, a significant drop in membrane CSF1R is useful for stratifying patients, beyond the power of cell categories published thus far, which fail to capture COVID-19 specific events. Importantly, CSF1R defines cells which are neither conventional monocytes nor DCs, which are missed in published analysis. CSF1R decrease can be linked <i>ex vivo</i> to high CSF1 levels. Blood assessment of CSF1R+ cells opens a developmental window to the Mononuclear Phagocyte System in transit from bone marrow to tissues, supports isolation and phenotypic characterisation, identifies novel cell types, and singles out CSF1R inhibition as therapeutic target in COVID-19 and other diseases.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab003"},"PeriodicalIF":4.1,"publicationDate":"2021-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40664157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrin-directed antibody-based immunotherapy: focus on VLA-4.","authors":"Wilson Savino,&nbsp;Beatriz Chaves,&nbsp;Adriana Cesar Bonomo,&nbsp;Vinicius Cotta-de-Almeida","doi":"10.1093/immadv/ltab002","DOIUrl":"https://doi.org/10.1093/immadv/ltab002","url":null,"abstract":"<p><p>One major finding of chronic inflammatory diseases of various origins is the establishment of inflammatory infiltrates, bearing different leukocyte subpopulations, including activated T lymphocytes. Integrins are among the large series of molecular interactions that have been implicated as players in both triggering and maintenance of leukocyte influx from the blood into a given organ parenchyme. Accordingly, blocking the interaction between VLA-6 integrin and laminin, experimentally abrogates heart graft rejection. Many reports have shown that VLA-4 is used by T cells to cross endothelial barriers, as well as to migrate within target tissues. In this respect, a humanized IgG4 anti-VLA-4 monoclonal antibody (specific to the α4-integrin chain of VLA-4) has been successfully applied to treat multiple sclerosis as well as inflammatory bowel disease. Anti-VLA-4 monoclonal antibody has also been applied to block transendothelial passage in other autoimmune diseases, such as rheumatoid arthritis. On this same vein is the action of such a reagent in impairing <i>in vitro</i> transendothial and fibronectin-driven migration of CD4⁺ and CD8⁺ T cells expressing high densities of VLA-4 from Duchenne muscular dystrophy patients, thus potentially enlarging the use of this strategy to other diseases. Yet, in a small number of patients, the use of Natalizumab has been correlated with the progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus. This issue restricted the use of the reagent. In this respect, the development of smaller and more specific antibody reagents should be envisioned as a next-generation promising strategy.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab002"},"PeriodicalIF":0.0,"publicationDate":"2021-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltab002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40578948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}