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1.
J Ovarian Res ; 17(1): 131, 2024 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-38909269

RESUMEN

BACKGROUND: This study aimed to develop and evaluate radiomics models to predict CD27 expression and clinical prognosis before surgery in patients with serous ovarian cancer (SOC). METHODS: We used transcriptome sequencing data and contrast-enhanced computed tomography images of patients with SOC from The Cancer Genome Atlas (n = 339) and The Cancer Imaging Archive (n = 57) and evaluated the clinical significance and prognostic value of CD27 expression. Radiomics features were selected to create a recursive feature elimination-logistic regression (RFE-LR) model and a least absolute shrinkage and selection operator logistic regression (LASSO-LR) model for CD27 expression prediction. RESULTS: CD27 expression was upregulated in tumor samples, and a high expression level was determined to be an independent protective factor for survival. A set of three and six radiomics features were extracted to develop RFE-LR and LASSO-LR radiomics models, respectively. Both models demonstrated good calibration and clinical benefits, as determined by the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. The LASSO-LR model performed better than the RFE-LR model, owing to the area under the curve (AUC) values of the ROC curves (0.829 vs. 0.736). Furthermore, the AUC value of the radiomics score that predicted the overall survival of patients with SOC diagnosed after 60 months was 0.788 using the LASSO-LR model. CONCLUSION: The radiomics models we developed are promising noninvasive tools for predicting CD27 expression status and SOC prognosis. The LASSO-LR model is highly recommended for evaluating the preoperative risk stratification for SOCs in clinical applications.


Asunto(s)
Neoplasias Ováricas , Tomografía Computarizada por Rayos X , Humanos , Femenino , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Pronóstico , Tomografía Computarizada por Rayos X/métodos , Persona de Mediana Edad , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Cistadenocarcinoma Seroso/diagnóstico por imagen , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/metabolismo , Anciano , Adulto , Curva ROC , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Radiómica
2.
EMBO J ; 43(14): 2878-2907, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38816652

RESUMEN

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αß-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C- cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C- cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C- cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.


Asunto(s)
Antígenos Ly , Receptores de Antígenos de Linfocitos T gamma-delta , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Animales , Ratones , Antígenos Ly/metabolismo , Antígenos Ly/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Humanos , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Interferón gamma/metabolismo , Interferón gamma/inmunología , Interleucina-27/metabolismo , Interleucina-27/genética , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo
3.
Immunity ; 57(2): 287-302.e12, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38354704

RESUMEN

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.


Asunto(s)
Antígenos CD28 , Redes Reguladoras de Genes , Factor 2 Asociado a Receptor de TNF/genética , Factor 2 Asociado a Receptor de TNF/metabolismo , Antígenos CD28/metabolismo , Transducción de Señal , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Ligando CD27/genética , Ligando CD27/metabolismo , Linfocitos T CD8-positivos
4.
Clin Cancer Res ; 28(22): 4983-4994, 2022 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-36067339

RESUMEN

PURPOSE: CD70 is a costimulatory molecule known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). Clear-cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors; however, the clinical consequences of CD70 expression remain unclear. EXPERIMENTAL DESIGN: Tumor tissue from 25 patients with ccRCC was assessed for the expression of CD27 and CD70 in situ using multiplex immunofluorescence. CD27+ T-cell phenotypes in tumors were analyzed by flow cytometry and their gene expression profile were analyzed by single-cell RNA sequencing then confirmed with public data. Baseline sCD27 was measured in 81 patients with renal cell carcinoma (RCC) treated with immunotherapy (35 for training cohort and 46 for validation cohort). RESULTS: In the tumor microenvironment, CD27+ T cells interacted with CD70-expressing tumor cells. Compared with CD27- T cells, CD27+ T cells exhibited an apoptotic and dysfunctional signature. In patients with RCC, the intratumoral CD27-CD70 interaction was significantly correlated with the plasma sCD27 concentration. High sCD27 levels predicted poor overall survival in patients with RCC treated with anti-programmed cell death protein 1 in both the training and validation cohorts but not in patients treated with antiangiogenic therapy. CONCLUSIONS: In conclusion, we demonstrated that sCD27, a surrogate marker of T-cell dysfunction, is a predictive biomarker of resistance to immunotherapy in RCC. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be extended to other tumors.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Ligando CD27/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Inmunoterapia , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Microambiente Tumoral
5.
Eur J Immunol ; 52(10): 1630-1639, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35862268

RESUMEN

In past years ex vivo and in vivo experimental approaches involving human naive B cells have proven fundamental for elucidation of mechanisms promoting B cell differentiation in both health and disease. For such studies, it is paramount that isolation strategies yield a population of bona fide naive B cells, i.e., B cells that are phenotypically and functionally naive, clonally non-expanded, and have non-mutated BCR variable regions. In this study different combinations of common as well as recently identified B cell markers were compared to isolate naive B cells from human peripheral blood. High-throughput BCR sequencing was performed to analyze levels of somatic hypermutation and clonal expansion. Additionally, contamination from mature mutated B cells intrinsic to each cell-sorting strategy was evaluated and how this impacts the purity of obtained populations. Our results show that current naive B cell isolation strategies harbor contamination from non-naive B cells, and use of CD27-IgD+ is adequate but can be improved by including markers for CD45RB glycosylation and IgM. The finetuning of naive B cell classification provided herein will harmonize research lines using naive B cells, and will improve B cell profiling during health and disease, e.g. during diagnosis, treatment, and vaccination strategies.


Asunto(s)
Subgrupos de Linfocitos B , Subgrupos de Linfocitos B/metabolismo , Separación Celular , Glicosilación , Humanos , Inmunoglobulina D/metabolismo , Isotipos de Inmunoglobulinas/metabolismo , Inmunoglobulina M/metabolismo , Memoria Inmunológica/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
6.
J Pediatr Hematol Oncol ; 44(4): e833-e843, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35398861

RESUMEN

This study aimed to report 4 siblings with CD27 deficiency presented with Hodgkin lymphoma. The father of the family, his 2 wives, and 17 children born from these wives were included into the study. CD27 mutation of all the family members with, and without Hodgkin lymphoma were studied. The variants detected by the exome sequencing analysis were verified by Sanger sequencing and analyzed using SeqScape Software 3. It was determined that both the father of the family and his 2 wives carried the same variant heterozygously. Of the children born to the first mother, 2 children were normal, 3 were heterozygous and 5 were homozygous. Four of these 5 homozygous children were diagnosed with Hodgkin lymphoma. Of the children born to the second mother, 1 child was normal, 3 children were heterozygous and 2 children were homozygous, and none of them had developed a malignant event. We also showed that CD27 deficiency may enhance Treg differentiation. According to our information, this study augmented the relationship of Hodgkin lymphoma and CD27 deficiency. The detection of homozygous CD27 variant in all siblings who developed lymphoma strengthened the place of this mutation in the etiology of Hodgkin lymphoma. In contrast, the presence of homozygous siblings with no malignant event suggested the possible contributions of environmental factors on the etiology.


Asunto(s)
Enfermedad de Hodgkin , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Femenino , Heterocigoto , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/genética , Homocigoto , Humanos , Masculino , Mutación , Linaje , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética
7.
Front Immunol ; 13: 825619, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35154145

RESUMEN

Young children and older adults suffer from enhanced susceptibility to infections with blood-borne pathogens. An essential step towards immunity is the establishment of a splenic marginal zone (sMZ), which is immature at below 2 years of age. At approximately 5 years of age, an adult level of protection is reached but wanes again in older adults. Although the infant sMZ is thought to contain mostly naïve B cells, memory B cells are recruited to and recirculate from the sMZ throughout life, and class-switched sMZ B cells dominate in older adults. For a better resolution of naïve versus memory B-cell subset accumulation in the sMZ, we performed a single cell-based gene expression analysis of (CD21highIgMhigh) sMZ B cells among five healthy donors (age 3 to 48 years) and validated the sMZ B-cell subset composition by flow cytometry of 147 spleen biopsies (age 0 to 82 years). We identified a major sMZ B-cell subpopulation, which is abundant at birth but decreases with age. These cells lack CD27 expression but carry a weak-to-intermediate memory B-cell signature. These CD27neg sMZ B cells are either IGHV-unmutated or carry only a few IGHV mutations early in life but show average memory B-cell IGHV mutation frequencies (>3%) in adults. The activation and proliferation potential of CD27neg sMZ B cells is significantly above that of non-sMZ B cells already in children. Our study suggests that the human sMZ B-cell pool changes with age, encompassing a major population of lowly Ig-mutated CD27neg but antigen-experienced B cells early in life.


Asunto(s)
Linfocitos B/inmunología , Cadenas Pesadas de Inmunoglobulina/inmunología , Bazo/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Adolescente , Adulto , Niño , Preescolar , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Persona de Mediana Edad , Mutación , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Adulto Joven
8.
Ital J Dermatol Venerol ; 157(3): 275-280, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34282858

RESUMEN

BACKGROUND: The etiopathogenesis of MF remains obscure. CD27 is a member of the tumor necrosis factor receptor superfamily (TNFRS) that regulates lymphocyte function. Expression of CD27 protein and mRNA has been reported in B-cell lymphomas and adult T-cell leukemia/lymphoma. In this study, we examined the expression of CD27 in the skin of MF patients by real time PCR. The amount of CD27 was measured in MF patients and healthy controls. METHODS: A total of 98 skin biopsies were analyzed: 12 obtained from healthy donors and 86 obtained cryostatic sections OCT-embedded affected by MF. Relative quantification of mRNA CD27 expression was achieved by means of TaqMan (Thermo Fisher Scientific, Waltham, MA, USA) amplification and normalization to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS: Housekeeping gene was detectable in all skin samples and there is no difference between healthy control and MF P value =0.1564. CD27 mRNA sequences were found in 3 of 12 (25%) of skin obtained from healthy donors and in 59 of 86 (68%) of skin obtained from cryostatic sections OCT-embedded affected by MF. The χ2 statistic with Yates correction is 6.8413 and the P value is 0.0089. When we compared the CD27 expression in MF and controls the RQ analysis showed a value of 9.12±14.13. A RQ of 9.12 means that this gene is 9.12 times more expressed in MF skin samples then in the healthy skin samples. No difference was observed in the MF clustered by stages. CONCLUSIONS: Our findings indicates that CD27 can be used as diagnostic/prognostic markers, and whether anti-CD27 antibodies can be used in therapy.


Asunto(s)
Leucemia-Linfoma de Células T del Adulto , Micosis Fungoide , Neoplasias Cutáneas , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Adulto , Humanos , Micosis Fungoide/genética , ARN Mensajero/genética , Piel/metabolismo , Neoplasias Cutáneas/genética
9.
Pathol Res Pract ; 228: 153665, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34717150

RESUMEN

Immunomodulatory signals regulate the self-tolerance, activation, priming and survival processes of T cells. Programmed cell death protein 1 (PD1), Programmed death-ligand 1 (PD-L1) inhibitory signals and CD27, CD28 costimulators have been detected for many solid organ cancers in tumor-infiltrating T cells. It was aimed to investigate the immune cell-based regulatory genetic variants in laryngeal squamous cell carcinoma (LSCC) in terms of clinicopathological features. Genotyping was performed by PCR-RFLP method for PD-1 rs2227981, PD-L1 rs2890658, CD28 rs3116496, CD27 rs2267966 genetic variants from genomic DNAs extracted from peripheral blood samples in One Hundred Thirty-Six individuals (Sixty-one LSCC and seventy-five controls). Analysis of SNPs was carried out according to multiple inheritance models (co-dominant, dominant, recessive, over-dominant and log-additive). There was no difference between LSCC and control groups in genotype/allele distribution for PD-1 and PD-L1 (p > 0.05). In the PD-1 overdominant model, the CT genotype was found to be high (p = 0.036) in those without a family history. The frequency of C allele (AC+CC) in the PD-L1 dominant model was higher in alcohol users and those with reflux (p = 0.024; p = 0.001 respectively). In the Dominant model for PD-L1, the AA genotype was lower in moderately and well-differentiated tumors than in poorly differentiated tumors (p = 0.02). CD27 AT and CD28 CT genotypes were found to be higher in LSCC patients compared to the control group (p = 0.009; p = 0.01 respectively), while linkage disequilibrium (LD) was detected between CD27 and CD28 (p = 0.02). In the CD28 dominant model, C allele (CT+CC) carriage was found to be high in those with family history and in those without reflux and perineural invasion (p = 0.01; p = 0.01; p = 0.03 respectively). In LSCC, PD-L1 rather than PD-1 has a prognostic effect in terms of clinicopathology, and the LD and clinicopathological relationships detected between CD28 and CD27 genotypes suggest that the hereditary immune checkpoint-dependent T cell traffic may be pathophysiologically important.


Asunto(s)
Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Microambiente Tumoral/inmunología , Anciano , Antígeno B7-H1/genética , Antígenos CD28/genética , Femenino , Genotipo , Neoplasias de Cabeza y Cuello/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptor de Muerte Celular Programada 1/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética
10.
Nat Commun ; 12(1): 5446, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34521844

RESUMEN

EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.


Asunto(s)
Ciclo Celular/genética , Linaje de la Célula/genética , Células Asesinas Naturales/inmunología , Proteínas de Dominio T Box/genética , Animales , Secuencia de Bases , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/inmunología , Diferenciación Celular , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/inmunología , Epigénesis Genética/inmunología , Interleucina-12/farmacología , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas , Unión Proteica , Bazo/citología , Bazo/inmunología , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/inmunología , Transcripción Genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
11.
J Biol Chem ; 297(4): 101102, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34419446

RESUMEN

CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro. These findings offer new mechanistic insight into this critical costimulatory interaction.


Asunto(s)
Ligando CD27/química , Complejos Multiproteicos/química , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/química , Ligando CD27/genética , Ligando CD27/inmunología , Cristalografía por Rayos X , Humanos , Complejos Multiproteicos/genética , Complejos Multiproteicos/inmunología , Estructura Cuaternaria de Proteína , Linfocitos T/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
12.
Cell Death Dis ; 12(6): 510, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-34006845

RESUMEN

Acute myeloid leukemia (AML) is a hematological malignancy with a low cure rate, especially in the elderly. Previous studies have shown that long non-coding RNA (lncRNA) may be an important factor in the pathogenesis of hematological malignancies, including acute myeloid leukemia (AML). However, the biological roles and clinical significances of most lncRNAs in AML are not fully understood. LncRNA CD27 Antisense RNA 1 (CD27-AS1), as a member of lncRNA family, has rare reports on its function. In present study, we found that the expression of CD27-AS1 examined by quantitative real-time PCR was markedly increased in the AML patients (N = 40) compared with healthy volunteers (N = 40). The overall survival time was significantly shorter in patients with higher CD27-AS1 expression than that in patients with lower CD27-AS1 (P < 0.01). Furthermore, downregulation of CD27-AS1 in AML cells suppressed proliferative ability, arrested cell cycle in G0/G1 phase, and induced apoptosis. However, CD27-AS1 overexpression further enhanced the malignant phenotype of AML cells. Additionally, CD27-AS1 was proved to increase PBX3 expression through sponging miR-224-5p. CD27-AS1 knockdown blocked the MAPK signaling through PBX3 silencing and further inhibited the cell growth of AML cells. Taken together, we demonstrate that CD27-AS1 may be a potential prognostic biomarker of AML, and our finding also provides a new insight for non-coding RNA-based therapeutic intervention of AML.


Asunto(s)
Proteínas de Homeodominio/metabolismo , Leucemia Mieloide Aguda/metabolismo , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , ARN Largo no Codificante/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Humanos , Leucemia Mieloide Aguda/genética , MicroARNs/genética , ARN sin Sentido/genética , ARN sin Sentido/metabolismo , ARN Largo no Codificante/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
13.
Eur J Med Genet ; 64(6): 104227, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33872774

RESUMEN

The identification of high-risk factors for the infection by SARS-CoV-2 and the negative outcome of COVID-19 is crucial. The genetic background of the host might account for individual responses to SARS-CoV-2 infection besides age and comorbidities. A list of candidate polymorphisms is needed to drive targeted screens, given the existence of frequent polymorphisms in the general population. We carried out text mining in the scientific literature to draw up a list of genes referable to the term "SARS-CoV*". We looked for frequent mutations that are likely to affect protein function in these genes. Ten genes, mostly involved in innate immunity, and thirteen common variants were identified, for some of these the involvement in COVID-19 is supported by publicly available epidemiological data. We looked for available data on the population distribution of these variants and we demonstrated that the prevalence of five of them, Arg52Cys (rs5030737), Gly54Asp (rs1800450) and Gly57Glu (rs1800451) in MBL2, Ala59Thr (rs25680) in CD27, and Val197Met (rs12329760) in TMPRSS2, correlates with the number of cases and/or deaths of COVID-19 observed in different countries. The association of the TMPRSS2 variant provides epidemiological evidence of the usefulness of transmembrane protease serine 2 inhibitors for the cure of COVID-19. The identified genetic variants represent a basis for the design of a cost-effective assay for population screening of genetic risk factors in the COVID-19 pandemic.


Asunto(s)
COVID-19/genética , COVID-19/inmunología , Predisposición Genética a la Enfermedad , Inmunidad Innata , SARS-CoV-2/patogenicidad , Minería de Datos , Frecuencia de los Genes , Variación Genética , Interacciones Microbiota-Huesped , Humanos , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
14.
Blood ; 137(23): 3225-3236, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-33827115

RESUMEN

Primary immunodeficiencies in the costimulatory molecule CD27 and its ligand, CD70, predispose for pathologies of uncontrolled Epstein-Barr virus (EBV) infection in nearly all affected patients. We demonstrate that both depletion of CD27+ cells and antibody blocking of CD27 interaction with CD70 cause uncontrolled EBV infection in mice with reconstituted human immune system components. While overall CD8+ T-cell expansion and composition are unaltered after antibody blocking of CD27, only some EBV-specific CD8+ T-cell responses, exemplified by early lytic EBV antigen BMLF1-specific CD8+ T cells, are inhibited in their proliferation and killing of EBV-transformed B cells. This suggests that CD27 is not required for all CD8+ T-cell expansions and cytotoxicity but is required for a subset of CD8+ T-cell responses that protect us from EBV pathology.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Inmunidad Celular , Fosfoproteínas/inmunología , Transactivadores/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Animales , Linfocitos B/inmunología , Transformación Celular Viral/genética , Transformación Celular Viral/inmunología , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Humanos , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Fosfoproteínas/genética , Transactivadores/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética
15.
Cancer Immunol Immunother ; 70(7): 2059-2071, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33439295

RESUMEN

Chimeric antigen receptor (CAR) T cell therapy, a type of adoptive cell therapy, has been successfully used when treating lymphoma malignancies, but not nearly as successful in treating solid tumors. Trophoblast cell surface antigen 2 (Trop2) is expressed in various solid tumors and plays a role in tumor growth, invasion, and metastasis. In this study, a CAR targeting Trop2 (T2-CAR) was developed with different co-stimulatory intercellular domains. T2-CAR T cells demonstrated a powerful killing ability in the presence of Trop2-positive cells following an in vitro assay. Moreover, T2-CAR T cells produced multiple effector cytokines under antigen stimulation. In tumor-bearing mouse models, the CD27-based T2-CAR T cells showed a higher antitumor activity. Additionally, more CD27-based T2-CAR T cells survived in tumor-bearing mice spleens as well as in the tumor tissue. CD27-based T2-CAR T cells were also found to upregulate IL-7Rα expression, while downregulating PD-1 expression. In conclusion, the CD27 intercellular domain can enhance the T2-CAR T cell killing effect via multiple mechanisms, thus indicating that a CD27-based T2-CAR T cell approach is suitable for clinical applications.


Asunto(s)
Neoplasias de la Mama/terapia , Moléculas de Adhesión Celular/antagonistas & inhibidores , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Apoptosis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto
16.
BMC Infect Dis ; 20(1): 948, 2020 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-33308178

RESUMEN

BACKGROUND: Dengue patients develop different disease severity ranging from mild (dengue fever [DF]) to severe forms (dengue hemorrhagic fever [DHF] and the fatal dengue shock syndrome [DSS]). Host genetics are considered to be one factor responsible for the severity of dengue outcomes. To identify genes associated with dengue severity that have not been studied yet, we performed genetic association analyses of interferon lambda 3 (IFNL3), CD27, and human leukocyte antigen-DPB1 (HLA-DPB1) genes in Thai dengue patients. METHODS: A case-control association study was performed in 877 children (age ≤ 15 years) with dengue infection (DF, n = 386; DHF, n = 416; DSS, n = 75). A candidate single nucleotide polymorphism of each of IFNL3, CD27, and HLA-DPB1 was selected to be analyzed. Genotyping was performed by TaqMan real-time PCR assay, and the association with dengue severity was examined. RESULTS: The rs9277534 variant of HLA-DPB1 was weakly associated with DHF. The genotype GG and G allele conferred protection against DHF (p = 0.04, odds ratio 0.74 for GG genotype, p = 0.03, odds ratio 0.79 for G allele). The association became borderline significant after adjusting for confounders (p = 0.05, odds ratio 0.82). No association was detected for IFNL3 or CD27. CONCLUSIONS: The present study demonstrated the weak association of the rs9277534 variant of HLA-DPB1 with protection against DHF. This variant is in the 3' untranslated region and affects HLA-DPB1 surface protein expression. Our finding suggests that HLA-DPB1 may be involved in DHF pathogenesis.


Asunto(s)
Virus del Dengue/genética , Virus del Dengue/inmunología , Cadenas beta de HLA-DP/genética , Interferones/genética , Dengue Grave/epidemiología , Dengue Grave/genética , Índice de Severidad de la Enfermedad , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Regiones no Traducidas 3'/genética , Adolescente , Alelos , Estudios de Casos y Controles , Niño , Virus del Dengue/aislamiento & purificación , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Dengue Grave/virología , Tailandia/epidemiología
17.
Int Immunopharmacol ; 89(Pt B): 107069, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33242709

RESUMEN

Current treatment of cholangiocarcinoma (CCA) - a lethal bile duct cancer - is ineffective because the disease is usually diagnosed at late and advanced stage. Thus, a novel therapeutic modality is urgently required. Fourth-generation chimeric antigen receptor (CAR4) T cells was created to target CD133, a well-known cancer stem cell marker, that is highly expressed and associates with cancer progression. The anti-CD133-CAR4 T cells showed high efficacy against CD133-expressing CCA cells. Tumour cell lysis occurred in a dose- and CD133 antigen-dependent manner, and significantly higher, up to 57.59% ± 9.62 at effector to target ratio of 5:1 in a CCA cell line - KKU-213A cells, compared to mock control (p = 0.008). Similarly, significant IFN-γ (p = 0.011) and TNF-α (p = 0.002) upregulation was observed upon tumour treatment. The effectiveness of our anti-CD133-CAR4 T cells will be beneficial not only for CD133-expressing CCA, but also for other CD133-expressing tumours. This study may guide future in vivo study and clinical trials.


Asunto(s)
Antígeno AC133/metabolismo , Neoplasias de los Conductos Biliares/terapia , Colangiocarcinoma/terapia , Inmunoterapia Adoptiva , Células Madre Neoplásicas/metabolismo , Anticuerpos de Cadena Única/metabolismo , Linfocitos T/metabolismo , Antígeno AC133/inmunología , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Antígenos CD28/genética , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Complejo CD3/genética , Complejo CD3/inmunología , Complejo CD3/metabolismo , Línea Celular Tumoral , Colangiocarcinoma/inmunología , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Humanos , Interferón gamma/metabolismo , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Anticuerpos de Cadena Única/genética , Anticuerpos de Cadena Única/inmunología , Esferoides Celulares , Linfocitos T/inmunología , Linfocitos T/trasplante , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
18.
Signal Transduct Target Ther ; 5(1): 192, 2020 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-32895366

Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Regulación de la Expresión Génica/inmunología , Linfopenia/inmunología , Neumonía Viral/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus/inmunología , Biomarcadores/sangre , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/mortalidad , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/mortalidad , Progresión de la Enfermedad , Femenino , Receptor 2 Celular del Virus de la Hepatitis A/sangre , Receptor 2 Celular del Virus de la Hepatitis A/genética , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/sangre , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Recuento de Linfocitos , Linfopenia/diagnóstico , Linfopenia/genética , Linfopenia/mortalidad , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/genética , Neumonía Viral/mortalidad , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Linfocitos T/virología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/sangre , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/sangre , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
19.
Exp Hematol ; 89: 55-60.e6, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32781097

RESUMEN

Despite recent identification of several prognostic markers, there is still a need for new prognostic parameters able to predict clinical outcome in chronic lymphocytic leukemia (CLL) patients. Here, we aimed to validate the prognostic ability of known (proteomic) markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL. To this end, baseline serum samples of 51 CLL patients treated with chemo-immunotherapy were analyzed for 360 proteomic markers, using Olink technology. Median event-free survival (EFS) was 23 months (range: 1.25-60.9). Patients with high levels of sCD23 (>11.27, p = 0.026), sCD27 (>11.03, p = 0.04), SPINT1 (>1.6, p = 0.001), and LY9 (>8.22, p = 0.0003) had a shorter EFS than those with marker levels below the median. The effect of sCD23 on EFS differed between immunoglobulin heavy chain variable gene-mutated and unmutated patients, with the shortest EFS for unmutated CLL patients with sCD23 levels above the median. Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients.


Asunto(s)
Biomarcadores de Tumor/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/terapia , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Receptores de IgE/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Clorambucilo , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/sangre , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoterapia/métodos , Lenalidomida , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Proteínas Inhibidoras de Proteinasas Secretoras/sangre , Proteómica/métodos , Receptores de IgE/sangre , Rituximab , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/sangre , Resultado del Tratamiento , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/sangre , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética
20.
J Hepatol ; 73(6): 1379-1390, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32649971

RESUMEN

BACKGROUND & AIMS: In most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies. In autoimmune hepatitis (AIH), the presence of anti-soluble liver antigen (SLA) autoantibodies is associated with reduced overall survival, but the associated autoreactive CD4 T cells have not yet been characterised. Herein, we isolated and deeply characterised SLA-specific CD4 T cells in patients with AIH. METHODS: We used brief ex vivo restimulation with overlapping SLA peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterise their transcriptome and T-cell receptor (TCR) repertoire. Autoreactive TCRs were cloned and used to identify dominant SLA-derived epitopes. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing to identify their phenotypic niche. We further characterised disease-associated peripheral blood T cells by high-content flow cytometry in 42 patients with AIH and 17 controls with non-alcoholic steatohepatitis. RESULTS: Autoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1+CXCR5-CCR6-CD27+ phenotype. ScRNA-seq revealed their pro-inflammatory/B-helper profile. SLA81-100 and SLA177-204 contain dominant T-cell epitopes. Autoreactive TCR clonotypes were predominantly found in the memory PD-1+CXCR5-CD4 T cells, which were significantly increased in the blood of patients with AIH and supported B-cell differentiation through IL-21. Finally, we identified specific T-cell phenotypes linked to disease activity and IgG level during AIH. CONCLUSIONS: We provide a deep characterisation of rare circulating autoreactive CD4 T cells and identify their peripheral reservoir in AIH. We also propose a specific phenotype of autoreactive T cells related to AIH disease activity, which will be essential to track, delineate, and potentially target these pathogenic cells. LAY SUMMARY: One principal characteristic of autoimmune hepatitis (AIH), like for many other autoimmune diseases, is the accumulation of autoantibodies produced by B lymphocytes following their interaction with autoreactive CD4 T lymphocytes. In this study, we identified and characterised with high resolution these CD4 T cells. This will be essential to track, delineate, and potentially target them during AIH.


Asunto(s)
Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Hepatitis Autoinmune , Adulto , Autoanticuerpos/inmunología , Linfocitos B/inmunología , Epítopos de Linfocito T/análisis , Femenino , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/patología , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores CXCR5/genética , Análisis de Secuencia de ARN , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética
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