101 results on '"Immune phenotypes"'
Search Results
2. Phenotypic and Immunological Characterization of Patients with Activated PI3Kδ Syndrome 1 Presenting with Autoimmunity.
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Li, Qifan, Wang, Wenjie, Wu, Qi, Zhou, Qinhua, Ying, Wenjing, Hui, Xiaoying, Sun, Bijun, Hou, Jia, Qian, Feng, Wang, Xiaochuan, and Sun, Jinqiao
- Abstract
Purpose: Autoimmunity is a significant feature of APDS1 patients. We aimed to explore the pathogenic immune phenotype and possible mechanisms of autoimmunity in APDS1 patients. Methods: The clinical records and laboratory data of 42 APDS1 patients were reviewed. Immunophenotypes were evaluated by multiparametric flow cytometry. Autoantibodies were detected via antigen microarray analysis. Results: A total of 42 children with PIK3CD gene mutations were enrolled. Immunological tests revealed increased proportions of effector memory cells (86%) and central memory cells (59%) among CD4+ T cells; increased proportions of effector memory cells (83%) and terminally differentiated effector memory T cells (38%) among CD8+ T cells. Fewer CD3+ T cells and B cells and higher IgG levels were reported in patients with autoimmunity. The proportion of Tregs was decreased, and the proportions of Th9, Tfh, and Tfr cells were increased in APDS1 patients. Among APDS1 patients, higher proportion of Th2 and Tfr cells were found in those with autoimmunity. The proportions of CD11c+ B and CD21lo B cells in patients with autoimmunity were significantly increased. Antigen microarray analysis revealed a wide range of IgG/IgM autoantibodies in patients with APDS1. In patients with autoimmunity, the proportion of Tfr might be positively correlated with autoantibodies. Conclusions: The pathogenic immune phenotype of APDS1 patients included (1) deceased CD3+ T-cell and B-cell counts and increased IgG levels in patients with autoimmunity, (2) an imbalanced T helper cell subset, (3) increased proportions of autoreactive B cells, and (4) distinct autoantibody reactivities in patients with autoimmunity. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Immune cell phenotype and function patterns across the life course in individuals from rural Uganda.
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Nalwoga, Angela, Nakibuule, Marjorie, Roshan, Romin, Mbonye, Moses Kwizera, Miley, Wendell, Whitby, Denise, Newton, Robert, Rochford, Rosemary, and Cose, Stephen
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CELL physiology ,BLOOD cell count ,KILLER cells ,T cells ,LIFE course approach ,B cells - Abstract
Background: To determine the pattern of immune cell subsets across the life span in rural sub-Saharan Africa (SSA), and to set a reference standard for cell subsets amongst Africans, we characterised the major immune cell subsets in peripheral blood including T cells, B cells, monocytes, NK cells, neutrophils and eosinophils, in individuals aged 3 to 89 years from Uganda. Methods: Immune phenotypes were measured using both conventional flow cytometry in 72 individuals, and full spectrum flow cytometry in 80 individuals. Epstein-Barr virus (EBV) IFN-g T cell responses were quantified in 332 individuals using an ELISpot assay. Full blood counts of all study participants were also obtained. Results: The percentages of central memory (TCM) and senescent CD4+ and CD8+ T cell subsets, effector memory (TEM) CD8+ T cells and neutrophils increased with increasing age. On the other hand, the percentages of naïve T (TN) and B (BN) cells, atypical B cells (BA), total lymphocytes, eosinophils and basophils decreased with increasing age. There was no change in CD4+ or CD8+ T effector memory RA (TEMRA) cells, exhausted T cells, NK cells and monocytes with age. Higher eosinophil and basophil percentages were observed in males compared to females. T cell function as measured by IFN-g responses to EBV increased with increasing age, peaking at 31-55 years. Conclusion: The percentages of cell subsets differ between individuals from SSA compared to those elsewhere, perhaps reflecting a different antigenic milieu. These results serve as a reference for normal values in this population. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Blood T cell phenotypes correlate with fatigue severity in post-acute sequelae of COVID-19.
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Pink, Isabell, Hennigs, Jan K., Ruhl, Louisa, Sauer, Andrea, Boblitz, Lennart, Huwe, Marie, Fuge, Jan, Falk, Christine S., Pietschmann, Thomas, de Zwaan, Martina, Prasse, Antje, Kluge, Stefan, Klose, Hans, Hoeper, Marius M., and Welte, Tobias
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RISK assessment ,T cells ,RESEARCH funding ,FATIGUE (Physiology) ,POST-acute COVID-19 syndrome ,IMMUNOGLOBULINS ,SEVERITY of illness index ,DESCRIPTIVE statistics ,MULTIVARIATE analysis ,LONGITUDINAL method ,CYTOMETRY ,PHENOTYPES ,COVID-19 ,DISEASE risk factors - Abstract
Purpose: Post-acute sequelae of COVID-19 (PASC) affect approximately 10% of convalescent patients. The spectrum of symptoms is broad and heterogeneous with fatigue being the most often reported sequela. Easily accessible blood biomarkers to determine PASC severity are lacking. Thus, our study aimed to correlate immune phenotypes with PASC across the severity spectrum of COVID-19. Methods: A total of 176 originally immunonaïve, convalescent COVID-19 patients from a prospective cohort during the first pandemic phase were stratified by initial disease severity and underwent clinical, psychosocial, and immune phenotyping around 10 weeks after first COVID-19 symptoms. COVID-19-associated fatigue dynamics were assessed and related to clinical and immune phenotypes. Results: Fatigue and severe fatigue were commonly reported irrespective of initial COVID-19 severity or organ-specific PASC. A clinically relevant increase in fatigue severity after COVID-19 was detected in all groups. Neutralizing antibody titers were higher in patients with severe acute disease, but no association was found between antibody titers and PASC. While absolute peripheral blood immune cell counts in originally immunonaïve PASC patients did not differ from unexposed controls, peripheral CD3
+ CD4+ T cell counts were independently correlated with fatigue severity across all strata in multivariable analysis. Conclusions: Patients were at similar risk of self-reported PASC irrespective of initial disease severity. The independent correlation between fatigue severity and blood T cell phenotypes indicates a possible role of CD4+ T cells in the pathogenesis of post-COVID-19 fatigue, which might serve as a blood biomarker. [ABSTRACT FROM AUTHOR]- Published
- 2024
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5. Autoimmune and neuropsychiatric phenotypes in a Mecp2 transgenic mouse model on C57BL/6 background.
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Yaxi Li, Shu Zhang, Chenling Tang, Bowen Yang, Atrooz, Fatin, Zhifeng Ren, Mohan, Chandra, Salim, Samina, and Tianfu Wu
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TRANSGENIC mice ,LABORATORY mice ,ANIMAL disease models ,GERMINAL centers ,SYSTEMIC lupus erythematosus ,PSYCHOLOGICAL manifestations of general diseases ,AUTOIMMUNE diseases - Abstract
Introduction: Systemic Lupus Erythematosus (SLE) impacts the central nervous system (CNS), leading to severe neurological and psychiatric manifestations known as neuropsychiatric lupus (NPSLE). The complexity and heterogeneity of clinical presentations of NPSLE impede direct investigation of disease etiology in patients. The limitations of existing mouse models developed for NPSLE obstruct a comprehensive understanding of this disease. Hence, the identification of a robust mouse model of NPSLE is desirable. Methods: C57BL/6 mice transgenic for human MeCP2 (B6.Mecp2Tg1) were phenotyped, including autoantibody profiling through antigen array, analysis of cellularity and activation of splenic immune cells through flow cytometry, and measurement of proteinuria. Behavioral tests were conducted to explore their neuropsychiatric functions. Immunofluorescence analyses were used to reveal altered neurogenesis and brain inflammation. Various signaling molecules implicated in lupus pathogenesis were examined using western blotting. Results: B6.Mecp2Tg1 exhibits elevated proteinuria and an overall increase in autoantibodies, particularly in female B6.Mecp2Tg1 mice. An increase in CD3+CD4+ T cells in the transgenic mice was observed, along with activated germinal center cells and activated CD11b+F4/80+ macrophages. Moreover, the transgenic mice displayed reduced locomotor activity, heightened anxiety and depression, and impaired short-term memory. Immunofluorescence analysis revealed IgG deposition and immune cell infiltration in the kidneys and brains of transgenic mice, as well as altered neurogenesis, activated microglia, and compromised blood-brain barrier (BBB). Additionally, protein levels of various key signaling molecules were found to be differentially modulated upon MeCP2 overexpression, including GFAP, BDNF, Albumin, NCoR1, mTOR, and NLRP3. Discussion: Collectively, this work demonstrates that B6.Mecp2Tg1 mice exhibit lupus-like phenotypes as well as robust CNS dysfunctions, suggesting its utility as a new animal model for NPSLE. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Identification of tumor immunophenotypes associated with immunotherapy response in bladder cancer.
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Liang, Hai‐qi, Liao, Nai‐kai, Yang, Shu‐bo, Wei, Qiu‐ju, Tan, Shu‐ting, Zhai, Gao‐qiang, Lu, Jiang‐ting, Huang, Yi‐cheng, Deng, Xiao‐bin, Mo, Lin‐jian, and Cheng, Ji‐wen
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BLADDER cancer , *DISEASE risk factors , *GENE expression , *RNA sequencing , *IMMUNOTHERAPY , *IMMUNE checkpoint proteins - Abstract
Objectives: This study aims to reveal immunophenotypes associated with immunotherapy response in bladder cancer, identify the signature genes of immune subtypes, and provide new molecular targets for improving immunotherapy response. Methods: Bladder cancer immunophenotypes were characterized in the bulk RNA sequencing dataset GSE32894 and Imvigor210, and gene expression signatures were established to identify the immunophenotypes. Expression of gene signatures were validated in single‐cell RNA sequencing dataset GSE145140 and human proteins expression data source. Investigation of Immunotherapy Response was performed in IMvigor210 dataset. Prognosis of tumor immunophenotypes was further analyzed. Results: Inflamed and immune‐excluded immunophenotypes were characterized based on the tumor immune cell scores. Risk score models that were established rely on RNA sequencing profiles and overall survival of bladder cancer cohorts. The inflamed tumors had lower risk scores, and the low‐risk tumors were more likely to respond to atezolizumab, receiving complete response/partial response (CR/PR). Patients who responded to atezolizumab had higher SRRM4 and lower NPHS1 and TMEM72 expression than the non‐responders. SRRM4 expression was a protective factor for bladder cancer prognosis, while the NPHS1 and TMEM72 showed the opposite pattern. Conclusion: This study provided a novel classification method for tumor immunophenotypes. Bladder cancer immunophenotypes can predict the response to immune checkpoint blockade. The immunophenotypes can be identified by the expression of signature genes. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Immune Phenotype and Postoperative Complications After Elective Surgery.
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Moris, Dimitrios, Barfield, Richard, Chan, Cliburn, Chasse, Scott, Stempora, Linda, Jichun Xie, Plichta, Jennifer K., Thacker, Julie, Harpole, David H., Purves, Todd, Lagoo-Deenadayalan, Sandhya, Hwang, Eun-Sil Shelley, and Kirk, Allan D.
- Abstract
Objectives: To characterize and quantify accumulating immunologic alterations, pre and postoperatively in patients undergoing elective surgical procedures. Background: Elective surgery is an anticipatable, controlled human injury. Although the human response to injury is generally stereotyped, individual variability exists. This makes surgical outcomes less predictable, even after standardized procedures, and may provoke complications in patients unable to compensate for their injury. One potential source of variation is found in immune cell maturation, with phenotypic changes dependent on an individual's unique, lifelong response to environmental antigens. Methods: We enrolled 248 patients in a prospective trial facilitating comprehensive biospecimen and clinical data collection in patients scheduled to undergo elective surgery. Peripheral blood was collected preoperatively, and immediately on return to the postanesthesia care unit. Postoperative complications that occurred within 30 days after surgery were captured. Results: As this was an elective surgical cohort, outcomes were generally favorable. With a median follow-up of 6 months, the overall survival at 30 days was 100%. However, 20.5% of the cohort experienced a postoperative complication (infection, readmission, or system dysfunction). We identified substantial heterogeneity of immune senescence and terminal differentiation phenotypes in surgical patients. More importantly, phenotypes indicating increased T-cell maturation and senescence were associated with postoperative complications and were evident preoperatively. Conclusions: The baseline immune repertoire may define an immune signature of resilience to surgical injury and help predict risk for surgical complications. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Immune cell phenotype and function patterns across the life course in individuals from rural Uganda
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Angela Nalwoga, Marjorie Nakibuule, Romin Roshan, Moses Kwizera Mbonye, Wendell Miley, Denise Whitby, Robert Newton, Rosemary Rochford, and Stephen Cose
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immune parameters ,immune phenotypes ,Epstein-Barr virus T cell responses ,Uganda ,lifecourse ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundTo determine the pattern of immune cell subsets across the life span in rural sub-Saharan Africa (SSA), and to set a reference standard for cell subsets amongst Africans, we characterised the major immune cell subsets in peripheral blood including T cells, B cells, monocytes, NK cells, neutrophils and eosinophils, in individuals aged 3 to 89 years from Uganda.MethodsImmune phenotypes were measured using both conventional flow cytometry in 72 individuals, and full spectrum flow cytometry in 80 individuals. Epstein-Barr virus (EBV) IFN-γ T cell responses were quantified in 332 individuals using an ELISpot assay. Full blood counts of all study participants were also obtained.ResultsThe percentages of central memory (TCM) and senescent CD4+ and CD8+ T cell subsets, effector memory (TEM) CD8+ T cells and neutrophils increased with increasing age. On the other hand, the percentages of naïve T (TN) and B (BN) cells, atypical B cells (BA), total lymphocytes, eosinophils and basophils decreased with increasing age. There was no change in CD4+ or CD8+ T effector memory RA (TEMRA) cells, exhausted T cells, NK cells and monocytes with age. Higher eosinophil and basophil percentages were observed in males compared to females. T cell function as measured by IFN-γ responses to EBV increased with increasing age, peaking at 31-55 years.ConclusionThe percentages of cell subsets differ between individuals from SSA compared to those elsewhere, perhaps reflecting a different antigenic milieu. These results serve as a reference for normal values in this population.
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- 2024
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9. Editorial: Characteristic clinical immune phenotypes and molecular mechanisms associated with inflammatory diseases
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Shuming Pan, Di Xie, Chengjin Gao, and Kun Xiong
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immune phenotypes ,molecular mechanisms ,inflammatory diseases ,sepsis ,innate immune ,adaptive immune ,Immunologic diseases. Allergy ,RC581-607 - Published
- 2024
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10. Papillary thyroid cancer immune phenotypes via tumor-infiltrating lymphocyte spatial analysis.
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Myungwoo Nam, Woojung Yang, Hye Sung Kim, Jewel Park, Gahee Park, Sukjun Kim, Sanghoon Song, Chan-Young Ock, Wang, Victor G., Chuang, Jeffrey H., and Young Kwang Chae
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THYROID cancer , *TUMOR-infiltrating immune cells , *PHENOTYPES , *LYMPHATIC metastasis , *IMMUNE response , *ARTIFICIAL intelligence - Abstract
Standard-of-care treatment options provide an excellent prognosis for papillary thyroid cancers (PTCs); however, approximately 10% of cases are advanced PTCs, resulting in less than 50% 5-year survival rates. Understanding the tumor microenvironment is essential for understanding cancer progression and investigating potential biomarkers for treatment, such as immunotherapy. Our study focused on tumor-infiltrating lymphocytes (TILs), which are the main effectors of antitumor immunity and related to the mechanism of immunotherapy. Using an artificial intelligence model, we analyzed the density of intratumoral and peritumoral TILs in the pathologic slides of The Cancer Genome Atlas PTC cohort. Tumors were classified into three immune phenotypes (IPs) based on the spatial distribution of TILs: immune-desert (48%), immune-excluded (34%), and inflamed (18%). Immune-desert IP was mostly characterized by RAS mutations, high thyroid differentiation score, and low antitumor immune response. Immune-excluded IP predominantly consisted of BRAF V600E-mutated tumors and had a higher rate of lymph node metastasis. Inflamed IP was characterized by a high antitumor immune response, as demonstrated by a high cytolytic score, immune-related cell infiltrations, expression of immunomodulatory molecules (including immunotherapy target molecules), and enrichment of immune-related pathways. This study is the first to investigate IP classification using TILs in PTC through a tissue-based approach. Each IP had unique immune and genomic profiles. Further studies are warranted to assess the predictive value of IP classification in advanced PTC patients treated with immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2023
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11. A SURVIVAL ANALYSIS ON THE IMMUNE LANDSCAPE OF PAEDIATRIC SOLID TUMOURS.
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Khushboo Shrivastava, Tongbram Soni Devi, Saket Verma, P. Jaiswal, and Tirumala Kanakadurga Sripati
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Pediatric cancer ,Neuroblastoma ,Osteosarcoma ,Immune phenotypes ,General works ,R5-130.5 ,Infectious and parasitic diseases ,RC109-216 ,Surgery ,RD1-811 ,Public aspects of medicine ,RA1-1270 - Abstract
Introduction: The functional orientation of the tumor microenvironment has been shown in large immunogenomic investigations to play a predictive role in adult solid tumors; however, the paediatric equivalent of this variable has received little attention. Method: For four paediatric tumor types (408 patients), Wilms tumor (WLM), neuroblastoma (NBL), os- teosarcoma (OS), clear cell sarcoma of the kidney (CCSK), and rhabdoid tumor of the kidney (RT), we carried out a thorough study of public RNAseq data (TARGET). We evaluated the Immunologic Constant of Rejection’s (ICR) capability to detect an active Th1/cytotoxic response. Additionally, we carried out gene set enrichment analysis (ssGSEA), grouped more than 100 immunological features with good characterization into distinct immune subtypes, and compared the results. Result: Higher ICR scores were linked to better OS and high-risk NBL without MYCN amplification survival, but worse WLM survival. The same four major modules previously discovered in adult tumors (TCGA) were revealed by clustering immunological characteristics. These modules classified paediatric patients into six immunological subtypes (S1–S6), each of which had a different prognosis for survival. The S2 cluster, which has low enrichment of the wound healing signature, high Th1, and low Th2 infiltrates, and the S4 cluster, which has the opposite characteristics, demonstrated the best overall survival. Increased T-cell infiltration and worse outcomes were linked to the WNT/Beta-catenin pathway in OS. Conclusion: We showed that extracranial paediatric tumors might be categorized by their immunological makeup, revealing parallels with tumors seen in adults. To find diagnostic and prognostic biomarkers and to find potential immune-responsive tumors, immunological factors may be investigated. Recommendations: Close disease surveillance and genetic evaluation are recommended for patients with certain solid tumors or particular predisposing conditions.
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- 2023
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12. Machine learning-based immune phenotypes correlate with STK11/KEAP1 co-mutations and prognosis in resectable NSCLC: a sub-study of the TNM-I trial.
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Rakaee, M., Andersen, S., Giannikou, K., Paulsen, E.-E., Kilvaer, T.K., Busund, L.-T.R., Berg, T., Richardsen, E., Lombardi, A.P., Adib, E., Pedersen, M.I., Tafavvoghi, M., Wahl, S.G.F., Petersen, R.H., Bondgaard, A.L., Yde, C.W., Baudet, C., Licht, P., Lund-Iversen, M., and Grønberg, B.H.
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CYTOTOXIC T cells , *NON-small-cell lung carcinoma , *MACHINE learning , *PHENOTYPES , *T cells - Abstract
We aim to implement an immune cell score model in routine clinical practice for resected non-small-cell lung cancer (NSCLC) patients (NCT03299478). Molecular and genomic features associated with immune phenotypes in NSCLC have not been explored in detail. We developed a machine learning (ML)-based model to classify tumors into one of three categories: inflamed, altered, and desert, based on the spatial distribution of CD8+ T cells in two prospective (n = 453; TNM-I trial) and retrospective (n = 481) stage I-IIIA NSCLC surgical cohorts. NanoString assays and targeted gene panel sequencing were used to evaluate the association of gene expression and mutations with immune phenotypes. Among the total of 934 patients, 24.4% of tumors were classified as inflamed, 51.3% as altered, and 24.3% as desert. There were significant associations between ML-derived immune phenotypes and adaptive immunity gene expression signatures. We identified a strong association of the nuclear factor-κB pathway and CD8+ T-cell exclusion through a positive enrichment in the desert phenotype. KEAP1 [odds ratio (OR) 0.27, Q = 0.02] and STK11 (OR 0.39, Q = 0.04) were significantly co-mutated in non-inflamed lung adenocarcinoma (LUAD) compared to the inflamed phenotype. In the retrospective cohort, the inflamed phenotype was an independent prognostic factor for prolonged disease-specific survival and time to recurrence (hazard ratio 0.61, P = 0.01 and 0.65, P = 0.02, respectively). ML-based immune phenotyping by spatial distribution of T cells in resected NSCLC is able to identify patients at greater risk of disease recurrence after surgical resection. LUADs with concurrent KEAP1 and STK11 mutations are enriched for altered and desert immune phenotypes. • A novel ML model was devised and validated for in situ immune phenotyping. • The ML-driven immune phenotypes served as an independent prognostic indicator. • LUADs featuring concurrent KEAP1 and STK11 mutations predominantly display altered or desert-like immune phenotypes. • In the desert phenotype, the enrichment of nuclear factor-κB signaling correlates with the exclusion of cytotoxic T cells. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Exploring Spatial Heterogeneity of Immune Cells in Nasopharyngeal Cancer.
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Sobti, Aastha, Sakellariou, Christina, Nilsson, Johan S., Askmyr, David, Greiff, Lennart, and Lindstedt, Malin
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TISSUE arrays , *STAINS & staining (Microscopy) , *B cells , *LEUCOCYTES , *MACROPHAGES , *KILLER cells , *GENE expression profiling , *RESEARCH funding , *TUMOR markers , *T cells , *MYELOID cells , *PHENOTYPES ,NASOPHARYNX tumors - Abstract
Simple Summary: Nasopharyngeal cancer (NPC) is a malignant tumor of the upper pharynx. In this study, we used multiplex tissue analysis combined with digital spatial profiling to map the immune heterogeneity of NPC. Forty-seven specified regions-of-interest (ROIs) with 49 target proteins were profiled across 30 cases of NPC for quantitative assessment of proteins related to CD45+ cells present in NPC tissue. Protein markers associated with B cells, NK cells, macrophages, and regulatory T cells were expressed at higher levels in 'immune-rich cancer cell islets' compared to the 'surrounding stromal leukocyte' regions. In contrast, biomarkers associated with suppressive populations of myeloid cells and exhausted T cells were overexpressed in 'surrounding stromal leukocytes' compared to 'immune-rich cancer cell islet' regions of the tumor. Moreover, findings regarding defined cancer phenotypes, such as 'inflamed', 'immune-excluded', and 'desert', were highlighted. In the 'inflamed' phenotype, compared with the other two phenotypes, markers associated with B cells, NK cells, macrophages, and myeloid cells were expressed at a higher level. On the other hand, in the 'immune-excluded' phenotype, markers associated with suppressive populations of myeloid cells and T cells were expressed at a higher level compared with 'inflamed' and 'desert' groups, while the 'desert' profile had greater levels of granulocyte markers and immune-regulatory markers. The results shed light on the cellular composition of NPCs and may aid in stratifying patients to treatment based on their immune microenvironment. Nasopharyngeal cancer (NPC) is a malignant tumor. In a recent publication, we described the presence and distribution of CD8+ T cells in NPC and used the information to identify 'inflamed', 'immune-excluded', and 'desert' immune phenotypes, where 'inflamed' and 'immune-excluded' NPCs were correlated with CD8 T cell infiltration and survival. Arguably, more detailed and, in particular, spatially resolved data are required for patient stratification and for the identification of new treatment targets. In this study, we investigate the phenotype of CD45+ leukocytes in the previously analyzed NPC samples by applying multiplexed tissue analysis to assess the spatial distribution of cell types and to quantify selected biomarkers. A total of 47 specified regions-of-interest (ROIs) were generated based on CD45, CD8, and PanCK morphological staining. Using the GeoMx® Digital Spatial Profiler (DSP), 49 target proteins were digitally quantified from the selected ROIs of a tissue microarray consisting of 30 unique NPC biopsies. Protein targets associated with B cells (CD20), NK cells (CD56), macrophages (CD68), and regulatory T cells (PD-1, FOXP3) were most differentially expressed in CD45+ segments within 'immune-rich cancer cell islet' regions of the tumor (cf. 'surrounding stromal leukocyte' regions). In contrast, markers associated with suppressive populations of myeloid cells (CD163, B7-H3, VISTA) and T cells (CD4, LAG3, Tim-3) were expressed at a higher level in CD45+ segments in the 'surrounding stromal leukocyte' regions (cf. 'immune-rich cancer cell islet' regions). When comparing the three phenotypes, the 'inflamed' profile (cf. 'immune-excluded' and 'desert') exhibited higher expression of markers associated with B cells, NK cells, macrophages, and myeloid cells. Myeloid markers were highly expressed in the 'immune-excluded' phenotype. Granulocyte markers and immune-regulatory markers were higher in the 'desert' profile (cf. 'inflamed' and 'immune-excluded'). In conclusion, this study describes the spatial heterogeneity of the immune microenvironment in NPC and highlights immune-related biomarkers in immune phenotypes, which may aid in the stratification of patients for therapeutic purposes. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Towards a consensus definition of immune exclusion in cancer.
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Tiwari, Ankur, Oravecz, Tamas, Dillon, Laura A., Italiano, Antoine, Audoly, Laurent, Fridman, Wolf Hervé, and Clifton, Guy Travis
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DEFINITIONS ,TUMOR microenvironment ,ANTINEOPLASTIC agents ,DISEASE progression ,CELL aggregation - Abstract
Background: The immune cell topography of solid tumors has been increasingly recognized as an important predictive factor for progression of disease and response to immunotherapy. The distribution pattern of immune cells in solid tumors is commonly classified into three categories - namely, "Immune inflamed", "Immune desert" and "Immune excluded" - which, to some degree, connect immune cell presence and positioning within the tumor microenvironment to anti-tumor activity. Materials and methods: In this review, we look at the ways immune exclusion has been defined in published literature and identify opportunities to develop consistent, quantifiable definitions, which in turn, will allow better determination of the underlying mechanisms that span cancer types and, ultimately, aid in the development of treatments to target these mechanisms. Results: The definitions of tumor immune phenotypes, especially immune exclusion, have largely been conceptual. The existing literature lacks in consistency when it comes to practically defining immune exclusion, and there is no consensus on a definition. Majority of the definitions use somewhat arbitrary cut-offs in an attempt to place each tumor into a distinct phenotypic category. Tumor heterogeneity is often not accounted for, which limits the practical application of a definition. Conclusions: We have identified two key issues in existing definitions of immune exclusion, establishing clinically relevant cut-offswithin the spectrum of immune cell infiltration as well as tumor heterogeneity. We propose an approach to overcome these limitations, by reporting the degree of immune cell infiltration, tying cut-offs to clinically meaningful outcome measures, maximizing the number of regions of a tumor that are analyzed and reporting the degree of heterogeneity. Thiswill allow for a consensus practical definition for operationalizing this categorization into clinical trial and signal-seeking endpoints. [ABSTRACT FROM AUTHOR]
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- 2023
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15. The immune landscape of solid pediatric tumors
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Shimaa Sherif, Jessica Roelands, William Mifsud, Eiman I. Ahmed, Christophe M. Raynaud, Darawan Rinchai, Abbirami Sathappan, Ata Maaz, Ayman Saleh, Erdener Ozer, Khalid A. Fakhro, Borbala Mifsud, Vésteinn Thorsson, Davide Bedognetti, and Wouter R. L. Hendrickx
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Pediatric cancer ,Neuroblastoma ,Osteosarcoma ,Immune phenotypes ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart. Methods We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome. Results A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS. Conclusions We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
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- 2022
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16. Multi‐omics data identified TP53 and LRP1B as key regulatory gene related to immune phenotypes via EPCAM in HCC
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Liang Shi, Jie Cao, Xin Lei, Yifen Shi, and Lili Wu
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hepatocellular carcinoma ,immune phenotypes ,LRP1B ,prognosis ,TP53 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Many studies showed that the prognosis of hepatocellular carcinoma (HCC) was significantly associated with the expressions of TP53 and LRP1B. However, the potential influence of the two genes on the malignant progression of HCC is still to be expounded. Methods According to the correlation analysis between immune cells and expression levels of TP53 and LRP1B, we filtered the immune cells to perform unsupervised clustering analysis. Integration of multi‐omic data analysis identified genetic alteration and epigenetic alteration. In addition, pathway analysis was used to explore the potential function of the differentially expressed mRNAs. According to the differentially expressed genes, we established an interaction network to seek the hub gene. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a prognosis model. Results The unsupervised clustering analysis showed that the cluster A1 showed the highest immune cell levels and the cluster B2 showed the lowest immune cell levels. Multi‐omics data analysis identified that somatic mutations, copy number variations, and DNA methylation levels had significant differences between cluster A1 and cluster B2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the upregulated mRNAs in the cluster A1 were mainly concentrated in T cell activation, external side of plasma membrane, receptor ligand activity, and cytokine−cytokine receptor interaction. Importantly, the EPCAM was identified as a critical node in the lncRNAs–miRNAs–mRNAs regulatory network correlated with the immune phenotypes. In addition, based on differentially expressed genes between cluster A1 and cluster B2, the prognostic model established by LASSO could predict the overall survival (OS) of HCC accurately. Conclusions The results indicated that the TP53 and LRP1B acted as the key genes in regulating the immune phenotypes of HCC via EPCAM.
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- 2022
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17. Towards a consensus definition of immune exclusion in cancer
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Ankur Tiwari, Tamas Oravecz, Laura A. Dillon, Antoine Italiano, Laurent Audoly, Wolf Hervé Fridman, and Guy Travis Clifton
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immune phenotypes ,immune exclusion ,tumor microenvironment ,immune cell topography ,cancer immunotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundThe immune cell topography of solid tumors has been increasingly recognized as an important predictive factor for progression of disease and response to immunotherapy. The distribution pattern of immune cells in solid tumors is commonly classified into three categories - namely, “Immune inflamed”, “Immune desert” and “Immune excluded” - which, to some degree, connect immune cell presence and positioning within the tumor microenvironment to anti-tumor activity.Materials and methodsIn this review, we look at the ways immune exclusion has been defined in published literature and identify opportunities to develop consistent, quantifiable definitions, which in turn, will allow better determination of the underlying mechanisms that span cancer types and, ultimately, aid in the development of treatments to target these mechanisms.ResultsThe definitions of tumor immune phenotypes, especially immune exclusion, have largely been conceptual. The existing literature lacks in consistency when it comes to practically defining immune exclusion, and there is no consensus on a definition. Majority of the definitions use somewhat arbitrary cut-offs in an attempt to place each tumor into a distinct phenotypic category. Tumor heterogeneity is often not accounted for, which limits the practical application of a definition.ConclusionsWe have identified two key issues in existing definitions of immune exclusion, establishing clinically relevant cut-offs within the spectrum of immune cell infiltration as well as tumor heterogeneity. We propose an approach to overcome these limitations, by reporting the degree of immune cell infiltration, tying cut-offs to clinically meaningful outcome measures, maximizing the number of regions of a tumor that are analyzed and reporting the degree of heterogeneity. This will allow for a consensus practical definition for operationalizing this categorization into clinical trial and signal-seeking endpoints.
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- 2023
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18. The immune landscape of solid pediatric tumors.
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Sherif, Shimaa, Roelands, Jessica, Mifsud, William, Ahmed, Eiman I., Raynaud, Christophe M., Rinchai, Darawan, Sathappan, Abbirami, Maaz, Ata, Saleh, Ayman, Ozer, Erdener, Fakhro, Khalid A., Mifsud, Borbala, Thorsson, Vésteinn, Bedognetti, Davide, and Hendrickx, Wouter R. L.
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- *
NEUROBLASTOMA , *WNT/BETA-catenin pathway , *KIDNEY tumors , *PROGNOSIS , *NEPHROBLASTOMA , *TUMORS - Abstract
Background: Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart. Methods: We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome. Results: A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS. Conclusions: We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults' tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Multi‐omics data identified TP53 and LRP1B as key regulatory gene related to immune phenotypes via EPCAM in HCC.
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Shi, Liang, Cao, Jie, Lei, Xin, Shi, Yifen, and Wu, Lili
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- *
REGULATOR genes , *SOMATIC mutation , *PHENOTYPES , *GENE clusters , *CANCER prognosis , *REGRESSION analysis , *CLUSTER analysis (Statistics) - Abstract
Background: Many studies showed that the prognosis of hepatocellular carcinoma (HCC) was significantly associated with the expressions of TP53 and LRP1B. However, the potential influence of the two genes on the malignant progression of HCC is still to be expounded. Methods: According to the correlation analysis between immune cells and expression levels of TP53 and LRP1B, we filtered the immune cells to perform unsupervised clustering analysis. Integration of multi‐omic data analysis identified genetic alteration and epigenetic alteration. In addition, pathway analysis was used to explore the potential function of the differentially expressed mRNAs. According to the differentially expressed genes, we established an interaction network to seek the hub gene. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a prognosis model. Results: The unsupervised clustering analysis showed that the cluster A1 showed the highest immune cell levels and the cluster B2 showed the lowest immune cell levels. Multi‐omics data analysis identified that somatic mutations, copy number variations, and DNA methylation levels had significant differences between cluster A1 and cluster B2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the upregulated mRNAs in the cluster A1 were mainly concentrated in T cell activation, external side of plasma membrane, receptor ligand activity, and cytokine−cytokine receptor interaction. Importantly, the EPCAM was identified as a critical node in the lncRNAs–miRNAs–mRNAs regulatory network correlated with the immune phenotypes. In addition, based on differentially expressed genes between cluster A1 and cluster B2, the prognostic model established by LASSO could predict the overall survival (OS) of HCC accurately. Conclusions: The results indicated that the TP53 and LRP1B acted as the key genes in regulating the immune phenotypes of HCC via EPCAM. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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20. Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease
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Xiaojing Chu, Martin Jaeger, Joep Beumer, Olivier B. Bakker, Raul Aguirre-Gamboa, Marije Oosting, Sanne P. Smeekens, Simone Moorlag, Vera P. Mourits, Valerie A. C. M. Koeken, Charlotte de Bree, Trees Jansen, Ian T. Mathews, Khoi Dao, Mahan Najhawan, Jeramie D. Watrous, Irma Joosten, Sonia Sharma, Hans J. P. M. Koenen, Sebo Withoff, Iris H. Jonkers, Romana T. Netea-Maier, Ramnik J. Xavier, Lude Franke, Cheng-Jian Xu, Leo A. B. Joosten, Serena Sanna, Mohit Jain, Vinod Kumar, Hans Clevers, Cisca Wijmenga, Mihai G. Netea, and Yang Li
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Metabolomics ,Genomics ,Immune phenotypes ,Integrative analysis ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors. Result We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn’s disease, suggesting it is a potential therapeutic target. Conclusion This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.
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- 2021
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21. Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment
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Rongqun Guo, Mengdie Lü, Fujiao Cao, Guanghua Wu, Fengcai Gao, Haili Pang, Yadan Li, Yinyin Zhang, Haizhou Xing, Chunyan Liang, Tianxin Lyu, Chunyan Du, Yingmei Li, Rong Guo, Xinsheng Xie, Wei Li, Delong Liu, Yongping Song, and Zhongxing Jiang
- Subjects
Acute myeloid leukemia ,Microenvironment ,Single-cell RNA sequencing ,Immune phenotypes ,Bone marrow ,Immune cells ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Background Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. Methods Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. Results We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. Conclusion Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.
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- 2021
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22. Old and New Biomarkers for Infection, Inflammation, and Autoimmunity in Treatment-Resistant Affective and Schizophrenic Spectrum Disorders.
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Scheiber, Christian, Schulz, Tanja, Schneider, Julian M., Bechter, Karl, and Schneider, E. Marion
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SCHIZOPHRENIA , *CEREBROSPINAL fluid , *AFFECT (Psychology) , *BIOMARKERS , *AUTOIMMUNITY , *CEREBROSPINAL fluid examination , *CHEMOTAXIS - Abstract
Affective (AF) and Schizophrenic (SZ) Spectrum disorders manifest with risk factors, involving inflammatory processes linked to infections and autoimmunity. This study searched for novel biomarkers in cerebrospinal fluid (CSF) and peripheral blood. A total of 29 AF and 39 SZ patients with treatment-resistant disease were included. In CSF, the chemokine IL-8 was significantly elevated in AF and SZ patients. IL-8 promotes chemotaxis by neutrophils and may originate from different tissues. S100B, a glia-derived brain damage marker, was higher in CSF from AF than SZ patients. Among the plasma-derived biomarkers, ferritin was elevated in AF and SZ. Soluble CD25, indicating Treg dysfunction, was higher in SZ than in AF patients. Interferon-γ, implying virus-specific immune activation, was positive in selective AF patients, only. Both groups showed elevated expression of immunosuppressive CD33 on monocytes, but higher amounts of CD123+ plasmacytoid dendritic cells were restricted to SZ. In conclusion, chemotactic IL-8 indicates neuronal stress and inflammation in the CSF of both groups. Novel plasma-derived biomarkers such as sCD25 and monocytic CD33 distinguish SZ from AF with an autoimmune phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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23. The Prognostic Value of FoxP3+ Tumour-Infiltrating Lymphocytes in Rectal Cancer Depends on Immune Phenotypes Defined by CD8+ Cytotoxic T Cell Density.
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Schnellhardt, Sören, Hirneth, Johannes, Büttner-Herold, Maike, Daniel, Christoph, Haderlein, Marlen, Hartmann, Arndt, Fietkau, Rainer, and Distel, Luitpold
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CYTOTOXIC T cells ,RECTAL cancer ,TUMOR-infiltrating immune cells ,REGULATORY T cells ,PROGNOSIS ,CD8 antigen - Abstract
Tumour-infiltrating FoxP3+ regulatory T cells have been identified as both positive and negative prognostic factors in colorectal cancer (CRC) and rectal cancer (RC). In this study we investigated whether immune phenotypes, defined by CD8+ cytotoxic T cell density, may influence the prognostic association of FoxP3+ T cell densities in RC. Tissue microarrays from 154 rectal cancer resections were immunohistochemically double stained for CD8 and FoxP3. CD8+ and FoxP3+ cell densities were measured in the stromal and intraepithelial compartment. Stromal FoxP3+ cell densities were not associated with 10-year overall survival (OS). In the "immune-desert" phenotype, defined by very low stromal CD8+ cell density, a high density of stromal FoxP3+ T cells displayed a tendency towards an association with decreased 10-year OS (p = 0.179). In "inflamed" tumours, defined by high intraepithelial CD8+ T cell infiltration, the opposite was the case and high stromal FoxP3+ T cell densities were a positive prognostic factor (p = 0.048). Additionally, patients with an increased FoxP3/CD8 cell density ratio demonstrated a strong trend towards decreased 10-year OS (p = 0.066). These contrasting findings suggest functional heterogeneity within the group of FoxP3+ T cells. They are consistent with experimental studies which reported suppressive and non-suppressive populations of FoxP3+ T cells in CRC. Furthermore, our study demonstrates that CD8 immunohistochemistry may act as an instrument to identify tumours infiltrated by possibly functionally differing FoxP3+ T cell subtypes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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24. Early inflammatory profiles predict maximal disease severity in COVID-19: An unsupervised cluster analysis.
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Kenny G, Saini G, Gaillard CM, Negi R, Alalwan D, Garcia Leon A, McCann K, Tinago W, Kelly C, Cotter AG, de Barra E, Horgan M, Yousif O, Gautier V, Landay A, McAuley D, Feeney ER, O'Kane C, and Mallon PW
- Abstract
Background: The inflammatory changes that underlie the heterogeneous presentations of COVID-19 remain incompletely understood. In this study we aimed to identify inflammatory profiles that precede the development of severe COVID-19, that could serve as targets for optimised delivery of immunomodulatory therapies and provide insights for the development of new therapies., Methods: We included individuals sampled <10 days from COVID-19 symptom onset, recruited from both inpatient and outpatient settings. We measured 61 biomarkers in plasma, including markers of innate immune and T cell activation, coagulation, tissue repair and lung injury. We used principal component analysis and hierarchical clustering to derive biomarker clusters, and ordinal logistic regression to explore associations between cluster membership and maximal disease severity, adjusting for known risk factors for severe COVID-19., Results: In 312 individuals, median (IQR) 7 (4-9) days from symptom onset, we found four clusters. Cluster 1 was characterised by low overall inflammation, cluster 2 was characterised by higher levels of growth factors and markers of endothelial activation (EGF, VEGF, PDGF, TGFα, PAI-1 and p -selectin). Cluster 3 and 4 both had higher overall inflammation. Cluster 4 had the highest levels of most markers including markers of innate immune activation (IL6, procalcitonin, CRP, TNFα), and coagulation (D-dimer, TPO), in contrast cluster 3 had the highest levels of alveolar epithelial injury markers (RAGE, ST2), but relative downregulation of growth factors and endothelial activation markers, suggesting a dysfunctional inflammatory pattern. In unadjusted and adjusted analysis, compared to cluster 1, cluster 3 had the highest odds of progressing to more severe disease (unadjusted OR (95%CI) 9.02 (4.53-17.96), adjusted OR (95%CI) 6.02 (2.70-13.39))., Conclusion: Early inflammatory profiles predicted subsequent maximal disease severity independent of risk factors for severe COVID-19. A cluster with downregulation of growth factors and endothelial activation markers, and early evidence of alveolar epithelial injury, had the highest risk of severe COVID-19., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patrick Mallon reports financial support was provided by 10.13039/501100001602Science Foundation Ireland. Patrick Mallon reports financial support was provided by Smurfit Kappa Group plc. Grace Kenny reports financial support was provided by United States Embassy in Ireland. Eoin Feeney, Paddy Mallon and Alan Landay reports a relationship with Gilead Sciences Inc that includes: board membership, consulting or advisory, and travel reimbursement. Eoin Feeney and Paddy Mallon reports a relationship with ViiV Healthcare that includes: consulting or advisory and travel reimbursement. Eoin Feeney reports a relationship with Vidacare Ireland that includes: consulting or advisory. Eoghan de Barra reports a relationship with Sanofi Pasteur Inc that includes: consulting or advisory. Eoghan de Barra reports a relationship with Pfizer Inc that includes: travel reimbursement. Paddy Mallon reports a relationship with MSD that includes: consulting or advisory and travel reimbursement. Paddy Mallon reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory and travel reimbursement. Alan Landay reports a relationship with Abbott Laboratories that includes: consulting or advisory. Cecilia O'Kane reports a relationship with Insmed Inc that includes: consulting or advisory. Cecilia O'Kane reports a relationship with California Institute of Regenerative Medicine that includes: board membership. Cecilia O'Kane and Danny McCauley reports a relationship with 10.13039/100018645MRC that includes: funding grants. Cecilia O'Kane and Danny McCauley reports a relationship with 10.13039/100010269Wellcome Trust that includes: funding grants. Cecilia O'Kane and Danny McCauley reports a relationship with National Institute of Health Sciences that includes: funding grants. Cecilia O'Kane and Danny McCauley reports a relationship with 10.13039/501100006041Innovate UK that includes: funding grants. Danny McCauley reports a relationship with 10.13039/100014101Novavax Inc that includes: funding grants. Danny McCauley reports a relationship with 10.13039/100004330GlaxoSmithKline that includes: consulting or advisory and speaking and lecture fees. Danny McCauley reports a relationship with Bayer that includes: consulting or advisory. Danny McAuley reports a relationship with Boehringer Ingelheim that includes: consulting or advisory. Danny McAuley reports a relationship with Novartis that includes: consulting or advisory. Danny McAuley reports a relationship with Eli Lilly and Company that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)
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- 2024
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25. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment
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Priyanka Devi-Marulkar, Carolina Moraes-Cabe, Pascal Campagne, Béatrice Corre, Aida Meghraoui-Kheddar, Vincent Bondet, Alba Llibre, Darragh Duffy, Elisabeth Maillart, Caroline Papeix, Sandra Pellegrini, and Frédérique Michel
- Subjects
multiple sclerosis ,type I interferon ,T cells ,interferon-stimulated genes ,HLA class II genes ,immune phenotypes ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundInterferon beta (IFNβ) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients.AimTo determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach.MethodsThe immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFNβ1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4+ T cells and naïve/memory T cell subsets, by measurement of circulating IFNα/β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DQA1, and -DQB1, using as a control population the Milieu Interieur cohort of 1,000 French healthy donors.ResultsClinical responders and non-responders displayed similar plasma levels of IFNβ and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFNβ, and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.
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- 2021
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26. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment.
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Devi-Marulkar, Priyanka, Moraes-Cabe, Carolina, Campagne, Pascal, Corre, Béatrice, Meghraoui-Kheddar, Aida, Bondet, Vincent, Llibre, Alba, Duffy, Darragh, Maillart, Elisabeth, Papeix, Caroline, Pellegrini, Sandra, and Michel, Frédérique
- Subjects
REGULATORY T cells ,MULTIPLE sclerosis ,INTERFERONS ,TYPE 1 diabetes ,CIRCULATING tumor DNA ,TREATMENT effectiveness - Abstract
Background: Interferon beta (IFN β) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients. Aim: To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFN β treatment using an integrated approach. Methods: The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFN β 1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4
+ T cells and naïve/memory T cell subsets, by measurement of circulating IFN α / β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA - DRB1, -DRB3,4,5, -DQA1 , and - DQB1 , using as a control population the Milieu Interieur cohort of 1,000 French healthy donors. Results: Clinical responders and non-responders displayed similar plasma levels of IFN β and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFN β , and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities. [ABSTRACT FROM AUTHOR]- Published
- 2021
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- View/download PDF
27. Old and New Biomarkers for Infection, Inflammation, and Autoimmunity in Treatment-Resistant Affective and Schizophrenic Spectrum Disorders
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Christian Scheiber, Tanja Schulz, Julian M. Schneider, Karl Bechter, and E. Marion Schneider
- Subjects
affective disorders ,schizophrenia ,cerebrospinal fluid ,biomarkers ,immune phenotypes ,monocytes ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Affective (AF) and Schizophrenic (SZ) Spectrum disorders manifest with risk factors, involving inflammatory processes linked to infections and autoimmunity. This study searched for novel biomarkers in cerebrospinal fluid (CSF) and peripheral blood. A total of 29 AF and 39 SZ patients with treatment-resistant disease were included. In CSF, the chemokine IL-8 was significantly elevated in AF and SZ patients. IL-8 promotes chemotaxis by neutrophils and may originate from different tissues. S100B, a glia-derived brain damage marker, was higher in CSF from AF than SZ patients. Among the plasma-derived biomarkers, ferritin was elevated in AF and SZ. Soluble CD25, indicating Treg dysfunction, was higher in SZ than in AF patients. Interferon-γ, implying virus-specific immune activation, was positive in selective AF patients, only. Both groups showed elevated expression of immunosuppressive CD33 on monocytes, but higher amounts of CD123+ plasmacytoid dendritic cells were restricted to SZ. In conclusion, chemotactic IL-8 indicates neuronal stress and inflammation in the CSF of both groups. Novel plasma-derived biomarkers such as sCD25 and monocytic CD33 distinguish SZ from AF with an autoimmune phenotype.
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- 2022
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28. Editorial: Characteristic clinical immune phenotypes and molecular mechanisms associated with inflammatory diseases.
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Pan S, Xie D, Gao C, and Xiong K
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- Phenotype, Immunity, Innate, Adaptive Immunity
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2024
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29. Autoimmune and neuropsychiatric phenotypes in a Mecp2 transgenic mouse model on C57BL/6 background.
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Li Y, Zhang S, Tang C, Yang B, Atrooz F, Ren Z, Mohan C, Salim S, and Wu T
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- Humans, Animals, Mice, Female, Mice, Transgenic, Mice, Inbred C57BL, Autoantibodies, Phenotype, Proteinuria, Methyl-CpG-Binding Protein 2 genetics, Lupus Vasculitis, Central Nervous System
- Abstract
Introduction: Systemic Lupus Erythematosus (SLE) impacts the central nervous system (CNS), leading to severe neurological and psychiatric manifestations known as neuropsychiatric lupus (NPSLE). The complexity and heterogeneity of clinical presentations of NPSLE impede direct investigation of disease etiology in patients. The limitations of existing mouse models developed for NPSLE obstruct a comprehensive understanding of this disease. Hence, the identification of a robust mouse model of NPSLE is desirable., Methods: C57BL/6 mice transgenic for human MeCP2 (B6. Mecp2
Tg1 ) were phenotyped, including autoantibody profiling through antigen array, analysis of cellularity and activation of splenic immune cells through flow cytometry, and measurement of proteinuria. Behavioral tests were conducted to explore their neuropsychiatric functions. Immunofluorescence analyses were used to reveal altered neurogenesis and brain inflammation. Various signaling molecules implicated in lupus pathogenesis were examined using western blotting., Results: B6. Mecp2Tg1 exhibits elevated proteinuria and an overall increase in autoantibodies, particularly in female B6. Mecp2Tg1 mice. An increase in CD3+ CD4+ T cells in the transgenic mice was observed, along with activated germinal center cells and activated CD11b+ F4/80+ macrophages. Moreover, the transgenic mice displayed reduced locomotor activity, heightened anxiety and depression, and impaired short-term memory. Immunofluorescence analysis revealed IgG deposition and immune cell infiltration in the kidneys and brains of transgenic mice, as well as altered neurogenesis, activated microglia, and compromised blood-brain barrier (BBB). Additionally, protein levels of various key signaling molecules were found to be differentially modulated upon MeCP2 overexpression, including GFAP, BDNF, Albumin, NCoR1, mTOR, and NLRP3., Discussion: Collectively, this work demonstrates that B6. Mecp2Tg1 mice exhibit lupus-like phenotypes as well as robust CNS dysfunctions, suggesting its utility as a new animal model for NPSLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Zhang, Tang, Yang, Atrooz, Ren, Mohan, Salim and Wu.)- Published
- 2024
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30. Understanding immune phenotypes in human gastric disease tissues by multiplexed immunohistochemistry
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Le Ying, Feng Yan, Qiaohong Meng, Xiangliang Yuan, Liang Yu, Bryan R. G. Williams, David W. Chan, Liyun Shi, Yugang Tu, Peihua Ni, Xuefeng Wang, Dakang Xu, and Yiqun Hu
- Subjects
Human gastric disease ,Immune phenotypes ,Multiplexed immunohistochemistry ,Medicine - Abstract
Abstract Background Understanding immune phenotypes and human gastric disease in situ requires an approach that leverages multiplexed immunohistochemistry (mIHC) with multispectral imaging to facilitate precise image analyses. Methods We developed a novel 4-color mIHC assay based on tyramide signal amplification that allowed us to reliably interrogate immunologic checkpoints, including programmed death-ligand 1 (PD-L1), cytotoxic T cells (CD8+T) and regulatory T cells (Foxp3), in formalin-fixed, paraffin-embedded tissues of various human gastric diseases. By observing cell phenotypes within the disease tissue microenvironment, we were able to determine specific co-localized staining combinations and various measures of cell density. Results We found that PD-L1 was expressed in gastric ulcer and in tumor cells (TCs), as well as in tumor-infiltrating immune cells (TIICs), but not in normal gastric mucosa or other gastric intraepithelial neoplastic tissues. Furthermore, we found no significant reduction in CD8+T cells, whereas the ratio of CD8+T:Foxp3 cells and CD8+T:PD-L1 cells was suppressed in tumor tissues and elevated in adjacent normal tissues. An unsupervised hierarchical analysis also identified correlations between CD8+T and Foxp3+ tumor-infiltrating lymphocyte (TIL) densities and average PD-L1 levels. Three main groups were identified based on the results of CD8+T:PD-L1 ratios in gastric tumor tissues. Furthermore, integrating CD8+T:Foxp3 ratios, which increased the complexity for immune phenotype status, revealed 6–7 clusters that enabled the separation of gastric cancer patients at the same clinical stage into different risk-group subsets. Conclusions Characterizing immune phenotypes in human gastric disease tissues via multiplexed immunohistochemistry may help guide PD-L1 clinical therapy. Observing unique disease tissue microenvironments can improve our understanding of immune phenotypes and cell interactions within these microenvironments, providing the ability to predict safe responses to immunotherapies.
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- 2017
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31. Immune phenotypes in individuals positive for antinuclear antibodies: The impact of race and ethnicity.
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Pisetsky, David S.
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- 2020
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32. The Troika Host–Pathogen–Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes
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Helder Novais Bastos, Nuno S. Osório, Sebastien Gagneux, Iñaki Comas, and Margarida Saraiva
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tuberculosis ,genotypic diversity ,immune phenotypes ,severity of disease ,inflammation ,microenvironments ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The already enormous burden caused by tuberculosis (TB) will be further aggravated by the association of this disease with modern epidemics, as human immunodeficiency virus and diabetes. Furthermore, the increasingly aging population and the wider use of suppressive immune therapies hold the potential to enhance the incidence of TB. New preventive and therapeutic strategies based on recent advances on our understanding of TB are thus needed. In particular, understanding the intricate network of events modulating inflammation in TB will help to build more effective vaccines and host-directed therapies to stop TB. This review integrates the impact of host, pathogen, and extrinsic factors on inflammation and the almost scientifically unexplored complexity emerging from the interactions between these three factors. We highlight the exciting data showing a contribution of this troika for the clinical outcome of TB and the need of incorporating it when developing novel strategies to rewire the immune response in TB.
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- 2018
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33. The Troika Host--Pathogen--Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes.
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Bastos, Helder Novais, Osório, Nuno S., Gagneux, Sebastien, Comas, Iñaki, and Saraiva, Margarida
- Subjects
TUBERCULOSIS treatment ,IMMUNOTHERAPY ,HOST-parasite relationships - Abstract
The already enormous burden caused by tuberculosis (TB) will be further aggravated by the association of this disease with modern epidemics, as human immunodeficiency virus and diabetes. Furthermore, the increasingly aging population and the wider use of suppressive immune therapies hold the potential to enhance the incidence of TB. New preventive and therapeutic strategies based on recent advances on our understanding of TB are thus needed. In particular, understanding the intricate network of events modulating inflammation in TB will help to build more effective vaccines and host-directed therapies to stop TB. This review integrates the impact of host, pathogen, and extrinsic factors on inflammation and the almost scientifically unexplored complexity emerging from the interactions between these three factors. We highlight the exciting data showing a contribution of this troika for the clinical outcome of TB and the need of incorporating it when developing novel strategies to rewire the immune response in TB. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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34. Additional file 1 of Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients [Dataset]
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Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Toscano-Guerra, Emily, Martínez-Gallo, Mónica, Arrese-Muñoz, Iria, Gine, Anna, Diaz, Noelia, Gabriel-Medina, Pablo, Riveiro-Barciela, Mar, Labrador-Horrillo, Moisés, Martínez-Valle, Fernando, Sánchez Montalvá, Adrián, Hernández-González, Manuel, Pujol Borrell, Ricardo, Rodríguez-Frías, Francisco, Ferrer, Roser, Thomson, Timothy M., Paciucci, Rosana, Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Toscano-Guerra, Emily, Martínez-Gallo, Mónica, Arrese-Muñoz, Iria, Gine, Anna, Diaz, Noelia, Gabriel-Medina, Pablo, Riveiro-Barciela, Mar, Labrador-Horrillo, Moisés, Martínez-Valle, Fernando, Sánchez Montalvá, Adrián, Hernández-González, Manuel, Pujol Borrell, Ricardo, Rodríguez-Frías, Francisco, Ferrer, Roser, Thomson, Timothy M., and Paciucci, Rosana
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- 2022
35. Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Toscano-Guerra, Emily, Martínez-Gallo, Mónica, Arrese-Muñoz, Iria, Gine, Anna, Diaz, Noelia, Gabriel-Medina, Pablo, Riveiro-Barciela, Mar, Labrador-Horrillo, Moisés, Martínez-Valle, Fernando, Sánchez Montalvá, Adrián, Hernández-González, Manuel, Pujol Borrell, Ricardo, Rodríguez-Frías, Francisco, Ferrer, Roser, Thomson, Timothy M., Paciucci, Rosana, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Toscano-Guerra, Emily, Martínez-Gallo, Mónica, Arrese-Muñoz, Iria, Gine, Anna, Diaz, Noelia, Gabriel-Medina, Pablo, Riveiro-Barciela, Mar, Labrador-Horrillo, Moisés, Martínez-Valle, Fernando, Sánchez Montalvá, Adrián, Hernández-González, Manuel, Pujol Borrell, Ricardo, Rodríguez-Frías, Francisco, Ferrer, Roser, Thomson, Timothy M., and Paciucci, Rosana
- Abstract
Background SARS-CoV-2 infection portends a broad range of outcomes, from a majority of asymptomatic cases to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty, and co-morbidities such as obesity, diabetes, and cardiovascular disease. A precise knowledge of the molecular and biological mechanisms that may explain the association of severe disease with male sex is still lacking. Here, we analyzed the relationship of serum testosterone levels and the immune cell skewing with disease severity in male COVID-19 patients. Methods Biochemical and hematological parameters of admission samples in 497 hospitalized male and female COVID-19 patients, analyzed for associations with outcome and sex. Longitudinal (in-hospital course) analyses of a subcohort of 114 male patients were analyzed for associations with outcome. Longitudinal analyses of immune populations by flow cytometry in 24 male patients were studied for associations with outcome. Results We have found quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients identified serum testosterone trajectories as the strongest predictor of survival (AUC of ROC = 92.8%, p < 0.0001) in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. In lethal cases, longitudinal determinations of serum luteinizing hormone (LH) and androstenedione levels did not follow physiological feedback patterns. Failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes. Conclusions Recovery or failure to reinstate testosterone levels is strongly associated with survival or death, respectively, from COVID-19 in male patients. Our data suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed
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- 2022
36. Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease
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Chu, Xiaojing, Jaeger, Martin, Beumer, Joep, Bakker, Olivier B., Aguirre-Gamboa, Raul, Oosting, Marije, Smeekens, Sanne P., Moorlag, Simone, Mourits, Vera P., Koeken, Valerie A. C. M., de Bree, Charlotte, Jansen, Trees, Mathews, Ian T., Dao, Khoi, Najhawan, Mahan, Watrous, Jeramie D., Joosten, Irma, Sharma, Sonia, Koenen, Hans J. P. M., Withoff, Sebo, Jonkers, Iris H., Netea-Maier, Romana T., Xavier, Ramnik J., Franke, Lude, Xu, Cheng-Jian, Joosten, Leo A. B., Sanna, Serena, Jain, Mohit, Kumar, Vinod, Clevers, Hans, Wijmenga, Cisca, Netea, Mihai G., and Li, Yang
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- 2021
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37. Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment
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Guo, Rongqun, Lü, Mengdie, Cao, Fujiao, Wu, Guanghua, Gao, Fengcai, Pang, Haili, Li, Yadan, Zhang, Yinyin, Xing, Haizhou, Liang, Chunyan, Lyu, Tianxin, Du, Chunyan, Li, Yingmei, Guo, Rong, Xie, Xinsheng, Li, Wei, Liu, Delong, Song, Yongping, and Jiang, Zhongxing
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- 2021
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38. Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment
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Rong Guo, Yongping Song, Fujiao Cao, Yingmei Li, Tianxin Lyu, Chunyan Liang, Delong Liu, Fengcai Gao, Yadan Li, Rongqun Guo, Guanghua Wu, Wei Li, Zhongxing Jiang, Chunyan Du, Haili Pang, Yinyin Zhang, Haizhou Xing, Mengdie Lü, and Xinsheng Xie
- Subjects
0301 basic medicine ,Microenvironment ,medicine.medical_treatment ,T cell ,Clinical Biochemistry ,Population ,T lymphocytes ,chemical and pharmacologic phenomena ,Immune phenotypes ,Biology ,Single-cell RNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,hemic and lymphatic diseases ,medicine ,Cytotoxic T cell ,Bone marrow ,education ,education.field_of_study ,Acute myeloid leukemia ,Research ,Biochemistry (medical) ,Immune cells ,lcsh:RM1-950 ,Myeloid leukemia ,Immunotherapy ,T helper cell ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Therapeutics. Pharmacology ,Myeloid cells ,Cancer research ,Molecular Medicine ,CD8 ,030215 immunology - Abstract
Background Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. Methods Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. Results We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. Conclusion Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.
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- 2021
39. Exploring Spatial Heterogeneity of Immune Cells in Nasopharyngeal Cancer
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Aastha Sobti, Christina Sakellariou, Johan S. Nilsson, David Askmyr, Lennart Greiff, and Malin Lindstedt
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Cancer Research ,Oncology ,nasopharyngeal cancer ,immune phenotypes ,spatial omics ,digital spatial profiling ,biomarker discovery ,immune cells - Abstract
Nasopharyngeal cancer (NPC) is a malignant tumor. In a recent publication, we described the presence and distribution of CD8+ T cells in NPC and used the information to identify ‘inflamed’, ‘immune-excluded’, and ‘desert’ immune phenotypes, where ‘inflamed’ and ‘immune-excluded’ NPCs were correlated with CD8 T cell infiltration and survival. Arguably, more detailed and, in particular, spatially resolved data are required for patient stratification and for the identification of new treatment targets. In this study, we investigate the phenotype of CD45+ leukocytes in the previously analyzed NPC samples by applying multiplexed tissue analysis to assess the spatial distribution of cell types and to quantify selected biomarkers. A total of 47 specified regions-of-interest (ROIs) were generated based on CD45, CD8, and PanCK morphological staining. Using the GeoMx® Digital Spatial Profiler (DSP), 49 target proteins were digitally quantified from the selected ROIs of a tissue microarray consisting of 30 unique NPC biopsies. Protein targets associated with B cells (CD20), NK cells (CD56), macrophages (CD68), and regulatory T cells (PD-1, FOXP3) were most differentially expressed in CD45+ segments within ‘immune-rich cancer cell islet’ regions of the tumor (cf. ‘surrounding stromal leukocyte’ regions). In contrast, markers associated with suppressive populations of myeloid cells (CD163, B7-H3, VISTA) and T cells (CD4, LAG3, Tim-3) were expressed at a higher level in CD45+ segments in the ‘surrounding stromal leukocyte’ regions (cf. ‘immune-rich cancer cell islet’ regions). When comparing the three phenotypes, the ‘inflamed’ profile (cf. ‘immune-excluded’ and ‘desert’) exhibited higher expression of markers associated with B cells, NK cells, macrophages, and myeloid cells. Myeloid markers were highly expressed in the ‘immune-excluded’ phenotype. Granulocyte markers and immune-regulatory markers were higher in the ‘desert‘ profile (cf. ‘inflamed’ and ‘immune-excluded’). In conclusion, this study describes the spatial heterogeneity of the immune microenvironment in NPC and highlights immune-related biomarkers in immune phenotypes, which may aid in the stratification of patients for therapeutic purposes.
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- 2023
40. Papillary thyroid cancer immune phenotypes via tumor-infiltrating lymphocyte spatial analysis.
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Nam M, Yang W, Kim HS, Park J, Park G, Kim S, Song S, Ock CY, Wang VG, Chuang JH, and Chae YK
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- Humans, Thyroid Cancer, Papillary pathology, Lymphocytes, Tumor-Infiltrating, Artificial Intelligence, Phenotype, Proto-Oncogene Proteins B-raf genetics, Mutation, Tumor Microenvironment, Thyroid Neoplasms pathology
- Abstract
Standard-of-care treatment options provide an excellent prognosis for papillary thyroid cancers (PTCs); however, approximately 10% of cases are advanced PTCs, resulting in less than 50% 5-year survival rates. Understanding the tumor microenvironment is essential for understanding cancer progression and investigating potential biomarkers for treatment, such as immunotherapy. Our study focused on tumor-infiltrating lymphocytes (TILs), which are the main effectors of antitumor immunity and related to the mechanism of immunotherapy. Using an artificial intelligence model, we analyzed the density of intratumoral and peritumoral TILs in the pathologic slides of The Cancer Genome Atlas PTC cohort. Tumors were classified into three immune phenotypes (IPs) based on the spatial distribution of TILs: immune-desert (48%), immune-excluded (34%), and inflamed (18%). Immune-desert IP was mostly characterized by RAS mutations, high thyroid differentiation score, and low antitumor immune response. Immune-excluded IP predominantly consisted of BRAF V600E-mutated tumors and had a higher rate of lymph node metastasis. Inflamed IP was characterized by a high antitumor immune response, as demonstrated by a high cytolytic score, immune-related cell infiltrations, expression of immunomodulatory molecules (including immunotherapy target molecules), and enrichment of immune-related pathways. This study is the first to investigate IP classification using TILs in PTC through a tissue-based approach. Each IP had unique immune and genomic profiles. Further studies are warranted to assess the predictive value of IP classification in advanced PTC patients treated with immunotherapy.
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- 2023
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41. The Prognostic Value of FoxP3+ Tumour-Infiltrating Lymphocytes in Rectal Cancer Depends on Immune Phenotypes Defined by CD8+ Cytotoxic T Cell Density
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Sören Schnellhardt, Johannes Hirneth, Maike Büttner-Herold, Christoph Daniel, Marlen Haderlein, Arndt Hartmann, Rainer Fietkau, and Luitpold Distel
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Rectal Neoplasms ,Immunology ,Forkhead Transcription Factors ,chemical and pharmacologic phenomena ,CD8 ,RC581-607 ,CD8-Positive T-Lymphocytes ,regulatory T cells ,immune phenotypes ,Immunophenotyping ,Lymphocytes, Tumor-Infiltrating ,Foxp3 ,Tumor Microenvironment ,Immunology and Allergy ,Humans ,Lymphocyte Count ,ddc:610 ,prognosis ,Immunologic diseases. Allergy ,rectal cancer ,TILs ,tumour-infiltrating lymphocytes ,Original Research - Abstract
Tumour-infiltrating FoxP3+ regulatory T cells have been identified as both positive and negative prognostic factors in colorectal cancer (CRC) and rectal cancer (RC). In this study we investigated whether immune phenotypes, defined by CD8+ cytotoxic T cell density, may influence the prognostic association of FoxP3+ T cell densities in RC. Tissue microarrays from 154 rectal cancer resections were immunohistochemically double stained for CD8 and FoxP3. CD8+ and FoxP3+ cell densities were measured in the stromal and intraepithelial compartment. Stromal FoxP3+ cell densities were not associated with 10-year overall survival (OS). In the “immune-desert” phenotype, defined by very low stromal CD8+ cell density, a high density of stromal FoxP3+ T cells displayed a tendency towards an association with decreased 10-year OS (p = 0.179). In “inflamed” tumours, defined by high intraepithelial CD8+ T cell infiltration, the opposite was the case and high stromal FoxP3+ T cell densities were a positive prognostic factor (p = 0.048). Additionally, patients with an increased FoxP3/CD8 cell density ratio demonstrated a strong trend towards decreased 10-year OS (p = 0.066). These contrasting findings suggest functional heterogeneity within the group of FoxP3+ T cells. They are consistent with experimental studies which reported suppressive and non-suppressive populations of FoxP3+ T cells in CRC. Furthermore, our study demonstrates that CD8 immunohistochemistry may act as an instrument to identify tumours infiltrated by possibly functionally differing FoxP3+ T cell subtypes.
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- 2022
42. Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Toscano-Guerra, Emily [0000-0003-2718-1684], Martínez-Gallo, Mónica [0000-0002-7340-2161], Gabriel-Medina, Pablo [0000-0003-3079-6364], Riveiro-Barciela, Mar [0000-0001-9309-2052], Martínez-Valle, Fernando [0000-0003-2673-2034], Hernández-González, Manuel [0000-0002-6932-5853], Rodríguez-Frías, Francisco [0000-0002-9128-7013], Pujol Borrell, Ricardo [0000-0001-7833-675X], Ferrer, Roser [0000-0002-8925-3172], Thomson, Timothy M. [0000-0002-4670-9440], Paciucci, Rosana [0000-0002-1087-6378], Toscano-Guerra, Emily, Martínez-Gallo, Mónica, Arrese-Muñoz, Iria, Gine, Anna, Diaz, Noelia, Gabriel-Medina, Pablo, Riveiro-Barciela, Mar, Labrador-Horrillo, Moisés, Martínez-Valle, Fernando, Hernández-González, Manuel, Rodríguez-Frías, Francisco, Pujol Borrell, Ricardo, Ferrer, Roser, Thomson, Timothy M., Paciucci, Rosana, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Toscano-Guerra, Emily [0000-0003-2718-1684], Martínez-Gallo, Mónica [0000-0002-7340-2161], Gabriel-Medina, Pablo [0000-0003-3079-6364], Riveiro-Barciela, Mar [0000-0001-9309-2052], Martínez-Valle, Fernando [0000-0003-2673-2034], Hernández-González, Manuel [0000-0002-6932-5853], Rodríguez-Frías, Francisco [0000-0002-9128-7013], Pujol Borrell, Ricardo [0000-0001-7833-675X], Ferrer, Roser [0000-0002-8925-3172], Thomson, Timothy M. [0000-0002-4670-9440], Paciucci, Rosana [0000-0002-1087-6378], Toscano-Guerra, Emily, Martínez-Gallo, Mónica, Arrese-Muñoz, Iria, Gine, Anna, Diaz, Noelia, Gabriel-Medina, Pablo, Riveiro-Barciela, Mar, Labrador-Horrillo, Moisés, Martínez-Valle, Fernando, Hernández-González, Manuel, Rodríguez-Frías, Francisco, Pujol Borrell, Ricardo, Ferrer, Roser, Thomson, Timothy M., and Paciucci, Rosana
- Abstract
Infection with SARS-CoV-2 portends a broad range of outcomes, from a majority of asymptomatic cases or mild clinical courses to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty and co-morbidities such as obesity, diabetes or cardiovascular disease. A precise knowledge is still lacking of the molecular and biological mechanisms that may explain the association of severe disease with male sex. Here, we show that testosterone trajectories are highly accurate individual predictors (AUC of ROC = 0.928, p < 0.0001) of survival in male COVID-19 patients. Longitudinal determinations of blood levels of luteinizing hormone (LH) and androstenedione suggest an early modest inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by either full recovery in survivors or a peripheral failure in lethal cases. Moreover, failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and decrease of non-classical monocytes. The strong association of recovery or failure to reinstate testosterone levels with survival or death from COVID-19 in male patients is suggestive of a significant role of testosterone status in the immune responses to COVID-19.
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- 2021
43. Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease
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Ian T. Mathews, Yang Li, Valerie A. C. M. Koeken, Sonia Sharma, Mihai G. Netea, Trees Jansen, Charlotte de Bree, Mahan Najhawan, Vera P. Mourits, Sebo Withoff, Olivier B. Bakker, Marije Oosting, Simone J.C.F.M. Moorlag, Jeramie D. Watrous, Vinod Kumar, Sanne P. Smeekens, Serena Sanna, Ramnik J. Xavier, Joep Beumer, Martin Jaeger, Hans J. P. M. Koenen, Lude Franke, Leo A. B. Joosten, Iris Jonkers, Raul Aguirre-Gamboa, Cisca Wijmenga, Romana T. Netea-Maier, Mohit Jain, Hans Clevers, Cheng-Jian Xu, Xiaojing Chu, Irma Joosten, Khoi Dao, Hubrecht Institute for Developmental Biology and Stem Cell Research, Molecular Neuroscience and Ageing Research (MOLAR), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover., TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany., and BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
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Male ,0301 basic medicine ,Metabolite ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Immune phenotypes ,Disease ,VARIANTS ,SUSCEPTIBILITY ,QH426-470 ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,RARE ,WIDE ASSOCIATION ,Biology (General) ,POLYUNSATURATED FATTY-ACIDS ,Genetics ,Alanine ,Arachidonic Acid ,Genomics ,Middle Aged ,CROHNS-DISEASE ,Healthy Volunteers ,Phenotype ,MENDELIAN RANDOMIZATION ,GENETIC-FACTORS ,Female ,Metabolic Networks and Pathways ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,EXPRESSION ,Adult ,Adolescent ,QH301-705.5 ,Quantitative Trait Loci ,Glutamic Acid ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Biology ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Metabolomics ,Immune system ,Metabolome ,Humans ,COMMON ,Aged ,Research ,Integrative analysis ,Immunity, Innate ,Human genetics ,Metabolic pathway ,030104 developmental biology ,chemistry ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Background Recent studies highlight the role of metabolites in immune diseases, but it remains unknown how much of this effect is driven by genetic and non-genetic host factors. Result We systematically investigate circulating metabolites in a cohort of 500 healthy subjects (500FG) in whom immune function and activity are deeply measured and whose genetics are profiled. Our data reveal that several major metabolic pathways, including the alanine/glutamate pathway and the arachidonic acid pathway, have a strong impact on cytokine production in response to ex vivo stimulation. We also examine the genetic regulation of metabolites associated with immune phenotypes through genome-wide association analysis and identify 29 significant loci, including eight novel independent loci. Of these, one locus (rs174584-FADS2) associated with arachidonic acid metabolism is causally associated with Crohn’s disease, suggesting it is a potential therapeutic target. Conclusion This study provides a comprehensive map of the integration between the blood metabolome and immune phenotypes, reveals novel genetic factors that regulate blood metabolite concentrations, and proposes an integrative approach for identifying new disease treatment targets.
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- 2021
44. Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients
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Veronika Weyerer, Pamela L. Strissel, Reiner Strick, Danijel Sikic, Carol I. Geppert, Simone Bertz, Fabienne Lange, Helge Taubert, Sven Wach, Johannes Breyer, Christian Bolenz, Philipp Erben, Bernd J. Schmitz-Draeger, Bernd Wullich, Arndt Hartmann, and Markus Eckstein
- Subjects
PD-L1 ,Blasenkrebs ,Urinary bladder neoplasms ,Drug therapy ,Lymphocytes, Tumor-infiltrating ,Programmed cell death 1 receptor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Antineoplastic agents ,Therapeutic use ,Article ,immune phenotypes ,Immuntherapie ,Bladder ,Cancer ,urothelial cancer ,Death-ligand 1 ,PD-1 ,bladder cancer ,Immunotherapy ,ddc:610 ,Atezolizumab ,Chemotherapie ,TILs ,DDC 610 / Medicine & health ,RC254-282 ,Urothelkrebs - Abstract
Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance. Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) were assessed with four PD-L1 assays. PD-L1 scoring results were correlated with data from a comprehensive digital-spatial immune-profiling panel using descriptive statistics, hierarchical clustering and uni-/multivariable survival analyses. Results: PD-L1 scoring algorithms are heterogeneous (agreements from 63.1% to 87.7%), and stems from different constellations of immune and tumor cells (IC/TC). While Ventana IC5% algorithm identifies tumors with high inflammation and favorable baseline prognosis, CPS10 and the TCarea25%/ICarea25% algorithm identify tumors with TC and IC expression. Spatially organized immune phenotypes, which correlate either with high PD-L1 IC expression and favorable prognosis or constitutive PD-L1 TC expression and poor baseline prognosis, cannot be resolved properly by PD-L1 algorithms. PD-L1 negative tumors with relevant immune infiltration can be detected by sTILs scoring on HE slides and digital CD8+ scoring. Conclusions: Contemporary PD-L1 scoring algorithms are not sufficient to resolve spatially distributed MIBC immune phenotypes and their clinical implications. A more comprehensive view of immune phenotypes along with the integration of spatial PD-L1 expression on IC and TC is necessary in order to stratify patients for ICI., publishedVersion
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- 2021
45. The Milieu Intérieur study — An integrative approach for study of human immunological variance.
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Thomas, Stéphanie, Rouilly, Vincent, Patin, Etienne, Alanio, Cécile, Dubois, Annick, Delval, Cécile, Marquier, Louis-Guillaume, Fauchoux, Nicolas, Sayegrih, Seloua, Vray, Muriel, Duffy, Darragh, Quintana-Murci, Lluis, and Albert, Matthew L.
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IMMUNE response , *BLOOD pressure measurement , *SINGLE nucleotide polymorphisms , *ACQUISITION of data , *IMMUNOLOGY , *COHORT analysis - Abstract
The Milieu Intérieur Consortium has established a 1000-person healthy population-based study (stratified according to sex and age), creating an unparalleled opportunity for assessing the determinants of human immunologic variance. Herein, we define the criteria utilized for participant enrollment, and highlight the key data that were collected for correlative studies. In this report, we analyzed biological correlates of sex, age, smoking-habits, metabolic score and CMV infection. We characterized and identified unique risk factors among healthy donors, as compared to studies that have focused on the general population or disease cohorts. Finally, we highlight sex-bias in the thresholds used for metabolic score determination and recommend a deeper examination of current guidelines. In sum, our clinical design, standardized sample collection strategies, and epidemiological data analyses have established the foundation for defining variability within human immune responses. [ABSTRACT FROM AUTHOR]
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- 2015
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46. Altered Immune Phenotypes and
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Priyanka, Devi-Marulkar, Carolina, Moraes-Cabe, Pascal, Campagne, Béatrice, Corre, Aida, Meghraoui-Kheddar, Vincent, Bondet, Alba, Llibre, Darragh, Duffy, Elisabeth, Maillart, Caroline, Papeix, Sandra, Pellegrini, and Frédérique, Michel
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Immunology ,T cells ,Genetic Variation ,blood biomarkers ,Middle Aged ,multiple sclerosis ,immune phenotypes ,HLA class II genes ,Young Adult ,Multiple Sclerosis, Relapsing-Remitting ,Phenotype ,interferon-stimulated genes ,Case-Control Studies ,Interferon Regulatory Factors ,HLA-DQ beta-Chains ,Humans ,Immunologic Factors ,type I interferon ,Female ,Treatment Failure ,Interferon beta-1a ,Original Research - Abstract
Background Interferon beta (IFNβ) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients. Aim To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach. Methods The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFNβ1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4+ T cells and naïve/memory T cell subsets, by measurement of circulating IFNα/β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DQA1, and -DQB1, using as a control population the Milieu Interieur cohort of 1,000 French healthy donors. Results Clinical responders and non-responders displayed similar plasma levels of IFNβ and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFNβ, and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.
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- 2020
47. Immunosenescence in the nursing home elderly.
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Johnstone, Jennie, Millar, Jamie, Lelic, Alina, Verschoor, Chris P., Walter, Stephen D., Devereaux, Philip J., Bramson, Jonathan, and Loeb, Mark
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IMMUNOSENESCENCE ,NURSING home residents ,OLDER patients ,IMMUNOSUPPRESSIVE agents ,CD4 antigen ,KILLER cells - Abstract
Background To describe T-cell and natural killer (NK) cell phenotypes within nursing home elderly. Methods Nursing home elderly were recruited from four nursing homes in Hamilton, Ontario between September 2010 and December 2011. Healthy adults were recruited from McMaster University between September 2011 and December 2011. Nursing home elderly ≥65 years were eligible; those on immunosuppressive medications were excluded. Healthy adults ≥18- 64 years were eligible. CD8+ and CD4+ T-cells% and their subsets, T-regs% and NK cell subset% were compared between the nursing home elderly and healthy adults. Results 262 nursing home elderly were enrolled; median age 87 years and 81% were female. 16 healthy adults were enrolled; median age 31 and 50% were female. There was no significant difference between CD8+ T-cell% in nursing home and healthy adults (median 17.1 versus 18.0, p = 0.56), however there were fewer naïve CD8 + T-cell% (median 0.9 versus 5.2, p < 0.001), more terminally differentiated CD8 + T-cell% (median 7.3 versus 4.1, p = 0.004) and more senescent T-cell% (median 5.3 versus 3.1, p = 0.04) in the nursing home elderly. There were more CD4+ T-cell% in the nursing home elderly compared to healthy adults (median 45.5 versus 37.1, p = 0.001). Nursing home elderly had a higher CD4+/CD8+ ratio than healthy adults (2.6 versus 1.9, p = 0.048), higher T-reg% (median 1.8 versus 0.8, p < 0.001) and increased mature NK cell% (median 12.1 versus 5.4, p = 0.001) compared to healthy adults. Conclusion Differences in naïve CD8+ T-cells, terminally differentiated and senescent CD8+ T-cells, Tregs and NK cell subsets were similar to studies involving community dwelling elderly. In contrast, the CD4+/CD8+ ratio was higher in nursing home elderly. [ABSTRACT FROM AUTHOR]
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- 2014
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48. DNA methylation regulator-mediated modification patterns and tumor microenvironment characterization in glioma.
- Author
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Luo H, Ye M, Hu Y, Wu M, Cheng M, Zhu X, and Huang K
- Subjects
- Humans, Tumor Microenvironment genetics, Programmed Cell Death 1 Receptor genetics, Immune Checkpoint Inhibitors, DNA Methylation, Glioma pathology
- Abstract
Growing evidences indicate DNA methylation plays a crucial regulatory role in inflammation, innate immunity, and immunotherapy. However, the overall landscape of various DNA methylation regulatory genes and their relationship with the infiltration of immune cells into the tumor microenvironment (TME) as well as the response to immunotherapy in gliomas is still not clear. Therefore, we comprehensively analyzed the correlation between DNA methylation regulator patterns, infiltration of immune cell-types, and tumor immune response status in gather glioma cohorts. Furthermore, we calculated the DNA methylation score (DMS) for individual glioma samples, then evaluated the relationship between DMS, clinicopathological characteristics, and overall survival (OS) in patients with gliomas. Our results showed three distinct DNA methylation regulator patterns among the glioma patients which correlated with three distinct tumor immune response phenotypes, namely, immune-inflamed, immune-excluded, and immune desert. We then calculated DMS for individual glioma samples based on the expression of DNA methylation-related gene clusters. Furthermore, DMS, tumor mutation burden (TMB), programmed death 1 (PD-1) expression, immune cell infiltration status in the TME, and Tumor Immune Dysfunction and Exclusion (TIDE) scores were associated with survival outcomes and clinical responses to immune checkpoint blockade therapy. We also validated the predictive value of DMS in two independent immunotherapy cohorts. In conclusion, our results demonstrated that three DNA methylation regulator patterns that correlated with three tumor immune response phenotypes. Moreover, we demonstrated that DMS was an independent predictive biomarker that correlated with survival outcomes of glioma patients and their responses to immunotherapy therapeutic regimens.
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- 2022
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49. The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy
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Jessica Roelands, Julie Decock, Ena Wang, Wouter Hendrickx, and Davide Bedognetti
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,breast cancer immunotherapy, immune phenotypes, MAP2K4 and MAP3K1 mutations, MAPK modulation, MEK inhibition, transcriptomics ,Immunology & Inflammation ,medicine.medical_treatment ,MAP2K4 ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,MAPK modulation ,03 medical and health sciences ,transcriptomics ,0302 clinical medicine ,Immune system ,Breast cancer ,medicine ,MAP2K4 and MAP3K1 mutations ,breast cancer immunotherapy ,Review Articles ,Cancer ,Tumor microenvironment ,business.industry ,Melanoma ,Immunotherapy ,Genomics ,medicine.disease ,immune phenotypes ,030104 developmental biology ,030220 oncology & carcinogenesis ,MEK inhibition ,Cancer research ,KRAS ,General Agricultural and Biological Sciences ,business - Abstract
With the advent of checkpoint inhibition, immunotherapy has revolutionized the clinical management of several cancers, but has demonstrated limited efficacy in mammary carcinoma. Transcriptomic profiling of cancer samples defined distinct immunophenotypic categories characterized by different prognostic and predictive connotations. In breast cancer, genomic alterations leading to the dysregulation of mitogen-activated protein kinase (MAPK) pathways have been linked to an immune-silent phenotype associated with poor outcome and treatment resistance. These aberrations include mutations of MAP3K1 and MAP2K4, amplification of KRAS, BRAF, and RAF1, and truncations of NF1. Anticancer therapies targeting MAPK signaling by BRAF and MEK inhibitors have demonstrated clear immunologic effects. These off-target properties could be exploited to convert the immune-silent tumor phenotype into an immune-active one. Preclinical evidence supports that MAPK-pathway inhibition can dramatically increase the efficacy of immunotherapy. In this review, we provide a detailed overview of the immunomodulatory impact of MAPK-pathway blockade through BRAF and MEK inhibitions. While BRAF inhibition might be relevant in melanoma only, MEK inhibition is potentially applicable to a wide range of tumors. Context-dependent similarities and differences of MAPK modulation will be dissected, in light of the complexity of the MAPK pathways. Therapeutic strategies combining the favorable effects of MAPK-oriented interventions on the tumor microenvironment while maintaining T-cell function will be presented. Finally, we will discuss recent studies highlighting the rationale for the implementation of MAPK-interference approaches in combination with checkpoint inhibitors and immune agonists in breast cancer.
- Published
- 2017
50. Gestational exposure to mercury leads to persistent changes in T-cell phenotype and function in adult DBF1 mice.
- Author
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Pilones, Karsten, Tatum, Arthur, and Gavalchin, Jerrie
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- *
MERCURY poisoning , *IMMUNOTOXICOLOGY , *T cells , *MICE , *PHENOTYPES , *CONTAMINATION of drinking water - Abstract
Previously, we showed that in utero exposure to mercury induced phenotypic changes in fetal immune cells. Here, we sought to determine whether the effects of in utero exposure on immune cells persisted in the adult. After overnight breeding to DBA/1 males, pregnant BALB/c dams were given either mercuric chloride in drinking water at 10 mg/L ad libitum for the duration of gestation or plain water. At the time of parturition, all dams were placed on regular drinking water. The pups (DBF1) were weaned and thymic and splenic tissues were harvested at 10 wk-of-age to assess T-cell phenotypes and function. Significant changes in the CD4/CD8 subsets in the thymus and spleen among mercury-exposed male and female mice were not observed. However, there was a significant reduction in splenic CD4+CD25+ cells in mercury-exposed female, but not in male, mice. ConA-stimulated splenocytes from mercury-exposed mice showed significant increases in proliferative responses relative to cells from control mice, regardless of sex. Cytokine secretion was also modulated in the mercury-exposed mice. In particular, the production of IL-4 and IFN by ConA-stimulated splenocytes from mercury-exposed male and female mice was significantly increased, while IL-2 and IL-10 levels were unaffected. The results of our study revealed that exposure of the developing immune system to relatively low levels of inorganic mercury could lead to persistent alterations in adult immune cell phenotypes and functions. These changes could pose a relevant health risk, if they contribute to impaired responses to pathogens and/or an increased risk for the development of atopy, asthma or possibly autoimmune diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
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