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1.
Immunity ; 57(2): 287-302.e12, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38354704

RESUMO

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.


Assuntos
Antígenos CD28 , Redes Reguladoras de Genes , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Antígenos CD28/metabolismo , Transdução de Sinais , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Ligante CD27/genética , Ligante CD27/metabolismo , Linfócitos T CD8-Positivos
2.
Front Immunol ; 14: 1252274, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965342

RESUMO

Introduction: T cell expressed CD27 provides costimulation upon binding to inducible membrane expressed trimeric CD70 and is required for protective CD8 T cell responses. CD27 agonists could therefore be used to bolster cellular vaccines and anti-tumour immune responses. To date, clinical development of CD27 agonists has focussed on anti-CD27 antibodies with little attention given to alternative approaches. Methods: Here, we describe the generation and activity of soluble variants of CD70 that form either trimeric (t) or dimer-of-trimer proteins and conduct side-by-side comparisons with an agonist anti-CD27 antibody. To generate a dimer-of-trimer protein (dt), we fused three extracellular domains of CD70 to the Fc domain of mouse IgG1 in a 'string of beads' configuration (dtCD70-Fc). Results: Whereas tCD70 failed to costimulate CD8 T cells, both dtCD70-Fc and an agonist anti-CD27 antibody were capable of enhancing T cell proliferation in vitro. Initial studies demonstrated that dtCD70-Fc was less efficacious than anti-CD27 in boosting a CD8 T cell vaccine response in vivo, concomitant with rapid clearance of dtCD70-Fc from the circulation. The accelerated plasma clearance of dtCD70-Fc was not due to the lack of neonatal Fc receptor binding but was dependent on the large population of oligomannose type glycosylation. Enzymatic treatment to reduce the oligomannose-type glycans in dtCD70-Fc improved its half-life and significantly enhanced its T cell stimulatory activity in vivo surpassing that of anti-CD27 antibody. We also show that whereas the ability of the anti-CD27 to boost a vaccine response was abolished in Fc gamma receptor (FcγR)-deficient mice, dtCD70-Fc remained active. By comparing the activity of dtCD70-Fc with a variant (dtCD70-Fc(D265A)) that lacks binding to FcγRs, we unexpectedly found that FcγR binding to dtCD70-Fc was required for maximal boosting of a CD8 T cell response in vivo. Interestingly, both dtCD70-Fc and dtCD70-Fc(D265A) were effective in prolonging the survival of mice harbouring BCL1 B cell lymphoma, demonstrating that a substantial part of the stimulatory activity of dtCD70-Fc in this setting is retained in the absence of FcγR interaction. Discussion: These data reveal that TNFRSF ligands can be generated with a tunable activity profile and suggest that this class of immune agonists could have broad applications in immunotherapy.


Assuntos
Receptores de IgG , Vacinas , Animais , Camundongos , Ligante CD27/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Imunização
3.
PLoS One ; 18(8): e0287738, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37531383

RESUMO

BACKGROUND: In the context of the current COVID-19 pandemic, there is still limited information about how people suffering from autoimmune diseases respond to the different COVID vaccines. The fact that they are taking an immunosuppressant or other drugs that aim to decrease the immune system activities, such as hydroxychloroquine (HCQ), could also impact their ability to respond to a COVID vaccine and vaccines in general. METHODS: Heathy donors were given 200mg of HCQ daily for 6-weeks to assess HCQs impact on the systemic T cells and humoral immune response. Peripheral blood mononuclear cells (PBMC) and plasma were obtained at baseline and 6-weeks after starting daily HCQ. Flow cytometry assays were designed to determine changes in T cell activation and T cell responses. Bead array multiplex were used to analyse antibodies and cytokine levels before and after HCQ intake. RESULTS: As anticipated, HCQ treatment decreased ex vivo T cell activation. We observed a decrease in CD4+CD161- expressing CCR5 (p = 0.015) and CD69 (p = 0.004) as well as in CD8+CCR5+ (p = 0.003), CD8+CD161+CCR5+ (p = 0.002) and CD8+CD161+CD95+ (p = 0.004). Additionally, HCQ decreased the proportion of Th17 expressing CD29 (p = 0.019), a subset associated with persistent inflammation. The proportion of T regulatory cells expressing the inhibitory molecule TIGIT was also reduced by HCQ (p = 0.003). As well, T cells from people on HCQ were less responsive to activation and cytokine production following stimulation with recall antigens and memory T cells were less likely to produce both IFNγ and TNFα following stimulation. CONCLUSION: This study shows HCQ is associated with lower T cell activation and decreased T cell cytokine production. While this study was not performed with the intent of looking at COVID vaccine response, it does provide important information about the changes in immune response that may occur in patient taking HCQ as a treatment for their autoimmune disease.


Assuntos
COVID-19 , Hidroxicloroquina , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Leucócitos Mononucleares , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Vacinas contra COVID-19 , Pandemias , Tratamento Farmacológico da COVID-19 , Citocinas
4.
J Immunol ; 211(3): 486-496, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37314411

RESUMO

The human lung carries a unique microbiome adapted to the air-filled, mucous-lined environment, the presence of which requires an immune system capable of recognizing harmful populations while preventing reactions toward commensals. B cells in the lung play a key role in pulmonary immunity, generating Ag-specific Abs, as well as cytokine secretion for immune activation and regulation. In this study, we compared B cell subsets in human lungs versus circulating cells by analyzing patient-paired lung and blood samples. We found a significantly smaller pool of CD19+, CD20+ B cells in the lung relative to the blood. CD27+, IgD-, class-switched memory B cells (Bmems) composed a larger proportion of the pool of pulmonary B cells. The residency marker CD69 was also significantly higher in the lung. We also sequenced the Ig V region genes (IgVRGs) of class-switched Bmems that do, or do not, express CD69. We observed the IgVRGs of pulmonary Bmems to be as heavily mutated from the unmutated common ancestor as those in circulation. Furthermore, we found progenies within a quasi-clone can gain or lose CD69 expression, regardless of whether the parent clone expressed the residency marker. Overall, our results show that despite its vascularized nature, human lungs carry a unique proportion of B cell subsets. The IgVRGs of pulmonary Bmems are as diverse as those in blood, and progenies of Bmems retain the ability to gain or lose residency.


Assuntos
Subpopulações de Linfócitos B , Memória Imunológica , Humanos , Linfócitos B , Genes de Imunoglobulinas , Antígenos CD19/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
5.
J Neuroimmunol ; 381: 578128, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37321014

RESUMO

Cerebrospinal fluid (CSF) soluble CD27 (sCD27) is a sensitive biomarker of intrathecal inflammation. Although generally considered a biomarker of T cell activation, CSF sCD27 has been shown to correlate with biomarkers of B cell activity in multiple sclerosis. We analyzed CSF from 40 patients with relapsing-remitting multiple sclerosis (RRMS) and nine symptomatic controls using flow cytometry and multiplex electrochemiluminescence immunoassays. CSF sCD27 levels were increased in RRMS and correlated with IgG index, soluble B cell maturation antigen, cell count, B cell frequency and CD8+ T cell frequency. We provide new data indicating that CSF sCD27 is associated with CD8+ T cells and B cells in RRMS.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Humanos , Linfócitos B , Biomarcadores/líquido cefalorraquidiano , Linfócitos T CD8-Positivos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/química , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
6.
Nat Commun ; 14(1): 1912, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-37024479

RESUMO

Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Animais , Camundongos , Linfócitos T Reguladores , Carcinoma Nasofaríngeo/genética , Ligante CD27/genética , Ligante CD27/metabolismo , Herpesvirus Humano 4/metabolismo , Neoplasias Nasofaríngeas/genética , Lipídeos , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Microambiente Tumoral
7.
Mol Imaging Biol ; 25(4): 621-629, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37012517

RESUMO

PURPOSE: The goal of this study was to develop an imaging probe-IRDye-680RD-OX40 mAb-that can be used for noninvasive imaging and optical imaging of rheumatoid arthritis (RA). OX40/OX40 ligand (OX40L) interactions have been shown to exert potent costimulatory effects on T cell activation. Detectable change in T cell activation profiles was observed in early RA. METHODS: OX40 expression pattern was analyzed by flow cytometry. N-hydroxysuccinimide (NHS) esters are used to label proteins selectively on free amino groups of OX40 monoclonal antibody (mAb). Characterization of IRDye-680RD-OX40 mAb was measured and a fluorescence spectrum gathered. Cell binding assay was also performed between activated and naïve murine T cells. Longitudinal near-infrared fluorescence (NIRF) imaging of the probe was performed on day 8, day 9, day 10, and day 11 of adjuvant-induced arthritis (AIA) mouse model. Paw thickness and body weight were compared between the OX40 mAb and IgG injection groups. RESULTS: NIRF imaging with IRDye-680RD-OX40 mAb revealed strong OX40-positive responses with high specificity. Flow analysis showed that OX40 was specifically expressed on the surface of T cells in RP and spleen of AIA model. The AIA group was significantly differentiated from the control group at all time points with imaging monitoring. The region of interest (ROI) was in line with ex vivo imaging and biodistribution study. This study highlights the potential utility of the OX40 NIRF imaging as a new strategy for RA prediction and T cell monitoring. CONCLUSION: The results provide evidence that IRDye-680RD-OX40 mAb detects organized T cells activation in early RA. The optical probe was capable of detection of RA pathogenesis. It identified transcriptional responses to RA that mediate its immune functions. Thus, it may be an ideal probe for RA imaging.


Assuntos
Artrite Reumatoide , Receptores do Fator de Necrose Tumoral , Camundongos , Animais , Receptores do Fator de Necrose Tumoral/metabolismo , Glicoproteínas de Membrana/metabolismo , Fatores de Necrose Tumoral/metabolismo , Receptores OX40/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Distribuição Tecidual , Linfócitos T/metabolismo , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Anticorpos Monoclonais/metabolismo
8.
Med Oncol ; 40(4): 123, 2023 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36944898

RESUMO

Chimeric antigen receptor T cell (CAR-T) is regarded as a promising therapy for malignancies. In our previous clinical trial targeted colorectal tumors, we found that CAR-T cells experienced poor proliferation and persistence in tumor sites. To improve the efficacy of CAR-T cells, we introduced CD27 co-stimulation signal into the established system and found that the CEA28BB27Z CAR-T cells exhibited enhanced proliferation and anti-tumor activity. Next, we demonstrated that the CEA28BB27Z CAR-T cells expressed less immune checkpoint receptors and generated more CD4+ and CD8+ memory stem T (TSCM) cells compared with other CARs during constant antigen stimulation. Furthermore, our data revealed that the different combination of co-stimulation signal affected the mitochondrial dynamics of CAR-T cells, and CEA28BB27Z CAR-T cells maintained more fused mitochondrial network compared with others. Finally, we validated the superior antitumor capacity of the CEA28BB27Z CAR-T cells in xenograft models. Our findings suggest that CD27 co-stimulation signals play a key role in improving the anti-tumor efficacy of CAR-T cells.


Assuntos
Neoplasias Colorretais , Receptores de Antígenos Quiméricos , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Humanos , Antígenos CD28/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Imunoterapia Adotiva , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
9.
Immunol Lett ; 255: 67-76, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36906182

RESUMO

Human B cells can be divided into four main subsets based on differential expression of immunoglobulin (Ig)D and CD27. IgD-CD27- double negative (DN) B cells make up a heterogeneous group of B cells that have first been described in relation to aging and systemic lupus erythematosus but have been mostly disregarded in B cell research. Over the last few years, DN B cells have gained a lot of interest because of their involvement in autoimmune and infectious diseases. DN B cells can be divided into different subsets that originate via different developmental processes and have different functional properties. Further research into the origin and function of different DN subsets is needed to better understand the role of these B cells in normal immune responses and how they could be targeted in specific pathologies. In this review, we give an overview of both phenotypic and functional properties of DN B cells and provide insight into the currently proposed origins of DN B cells. Moreover, their involvement in normal aging and different pathologies is discussed.


Assuntos
Subpopulações de Linfócitos B , Lúpus Eritematoso Sistêmico , Humanos , Linfócitos B , Envelhecimento , Memória Imunológica , Imunoglobulina D/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
10.
Front Immunol ; 14: 1023064, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36993956

RESUMO

Introduction: Most T lymphocytes, including regulatory T cells, express the CD27 costimulatory receptor in steady state conditions. There is evidence that CD27 engagement on conventional T lymphocytes favors the development of Th1 and cytotoxic responses in mice and humans, but the impact on the regulatory lineage is unknown. Methods: In this report, we examined the effect of constitutive CD27 engagement on both regulatory and conventional CD4+ T cells in vivo, in the absence of intentional antigenic stimulation. Results: Our data show that both T cell subsets polarize into type 1 Tconvs or Tregs, characterized by cell activation, cytokine production, response to IFN-γ and CXCR3-dependent migration to inflammatory sites. Transfer experiments suggest that CD27 engagement triggers Treg activation in a cell autonomous fashion. Conclusion: We conclude that CD27 may regulate the development of Th1 immunity in peripheral tissues as well as the subsequent switch of the effector response into long-term memory.


Assuntos
Subpopulações de Linfócitos T , Linfócitos T Reguladores , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Animais , Humanos , Camundongos , Antígenos/metabolismo , Ligante CD27/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
11.
Melanoma Res ; 33(2): 116-125, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36735464

RESUMO

Uveal melanoma represents an aggressive tumor that responds mostly poorly to established melanoma treatments. Comprehensive methylation profiling of the next-generation immunotherapeutic target genes, for example, members of the tumor necrosis factor receptor superfamily, might allow for the development of companion predictive biomarkers. We have analyzed CpG sites within the immune checkpoint genes GITR, OX40, 4-1BB, CD 27, and CD40 probed by the Illumina Infinium HumanMethylation450 BeadChip in N = 80 uveal melanomas included in The Cancer Genome Atlas with regard to BAP1 aberrancy, mRNA expression, and overall survival. In all analyzed immune checkpoint genes, BAP1 aberrancy was associated with decreased CpG methylation levels. We identified specific CpG sites that significantly correlated with BAP1 aberrancy, mRNA expression levels, and overall survival. Our results suggest epigenetic regulation of the analyzed immune checkpoint genes via DNA methylation in uveal melanoma and provide rationale for methylation testing in biomarker programs in clinical trials.


Assuntos
Melanoma , Neoplasias Cutâneas , Neoplasias Uveais , Humanos , Metilação de DNA , Epigênese Genética , Melanoma/patologia , Prognóstico , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/patologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Antígenos CD40
12.
Cancer Immunol Immunother ; 72(7): 2087-2098, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36811663

RESUMO

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein-Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma de Células T , Humanos , Ligante CD27 , Herpesvirus Humano 4/metabolismo , Biomarcadores , Células Matadoras Naturais/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral
13.
Funct Integr Genomics ; 23(1): 48, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36700974

RESUMO

The immune checkpoint molecule CD70 and its receptor CD27 constitute the signal transduction axis, which is abnormally expressed in many solid tumors and is crucial for T cell co-stimulation and immune escape. Tumor cells regulate CD27 expression in the tumor microenvironment by expressing CD70, which promotes immune escape. Although current research evidence suggests a link between CD70 and tumors, no pan-cancer analysis is available. Using the Cancer Genome Atlas, Gene Expression Omnibus datasets, and online databases, we first explored the potential carcinogenic role of the CD70-CD27 signaling axis in human malignancies. Furthermore, qRT-PCR, Western blot, immunohistochemistry, and a T cell-mediated tumor cell killing assay were used to assess the biological function of the CD70-CD27 signaling axis. CD70 expression is upregulated in most cancers and has an obvious correlation with the prognosis of tumor patients. The expression of CD70 and CD27 is associated with the level of regulatory T cell (Treg) infiltration. In addition, T cell receptor signaling pathways, PI3K-AKT, NF-κB, and TNF signaling pathways are also involved in CD70-mediated immune escape. CD70 mainly regulates tumor immune escape by regulating T cell-mediated tumor killing, with Tregs possibly being its primary T cell subset. Our first pan-cancer study provides a relatively comprehensive understanding of the carcinogenic role of the CD70-CD27 signaling axis in different tumors.


Assuntos
Neoplasias , Fosfatidilinositol 3-Quinases , Humanos , Ligante CD27/genética , Ligante CD27/metabolismo , Imunidade , Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Microambiente Tumoral , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
14.
Clin Exp Immunol ; 213(2): 164-172, 2023 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-36508329

RESUMO

Immunological memory protects the human body from re-infection with an earlier recognized pathogen. This memory comprises the durable serum antibody titres provided by long-lived plasma cells and the memory T and B cells with help from other cells. Memory B cells are the main precursor cells for new plasma cells during a secondary infection. Their formation starts very early in life, and they continue to form and undergo refinements throughout our lifetime. While the heterogeneity of the human memory B-cell pool is still poorly understood, specific cellular surface markers define most of the cell subpopulations. CD27 is one of the most commonly used markers to define human memory B cells. In addition, there are molecular markers, such as somatic mutations in the immunoglobulin heavy and light chains and isotype switching to, for example, IgG. Although not every memory B cell undergoes somatic hypermutation or isotype switching, most of them express these molecular traits in adulthood. In this review, I will focus on the most recent knowledge regarding CD27+ human memory B cells in health and disease, and describe how Ig sequencing can be used as a tool to decipher the evolutionary pathways of these cells.


Assuntos
Subpopulações de Linfócitos B , Células B de Memória , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Humanos , Linfócitos B , Switching de Imunoglobulina , Isotipos de Imunoglobulinas , Memória Imunológica , Plasmócitos/metabolismo , Hipermutação Somática de Imunoglobulina , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
15.
Clin Cancer Res ; 28(22): 4983-4994, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36067339

RESUMO

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.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Ligante CD27/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Imunoterapia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Microambiente Tumoral
16.
J Immunother Cancer ; 10(9)2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36100308

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICI) have radically changed cancer therapy, but most patients with cancer are unresponsive or relapse after treatment. MK-5890 is a CD27 agonist antibody intended to complement ICI therapy. CD27 is a member of the tumor necrosis factor receptor superfamily that plays a critical role in promoting responses of T cells, B cells and NK cells. METHODS: Anti-CD27 antibodies were generated and selected for agonist activity using NF-кB luciferase reporter assays. Antibodies were humanized and characterized for agonism using in vitro T-cell proliferation assays. The epitope recognized on CD27 by MK-5890 was established by X-ray crystallography. Anti-tumor activity was evaluated in a human CD27 knock-in mouse. Preclinical safety was tested in rhesus monkeys. Pharmacodynamic properties were examined in mouse, rhesus monkeys and a phase 1 dose escalation clinical study in patients with cancer. RESULTS: Humanized anti-CD27 antibody MK-5890 (hIgG1) was shown to bind human CD27 on the cell surface with sub-nanomolar potency and to partially block binding to its ligand, CD70. Crystallization studies revealed that MK-5890 binds to a unique epitope in the cysteine-rich domain 1 (CRD1). MK-5890 activated CD27 expressed on 293T NF-κB luciferase reporter cells and, conditional on CD3 stimulation, in purified CD8+ T cells without the requirement of crosslinking. Functional Fc-receptor interaction was required to activate CD8+ T cells in an ex vivo tumor explant system and to induce antitumor efficacy in syngeneic murine subcutaneous tumor models. MK-5890 had monotherapy efficacy in these models and enhanced efficacy of PD-1 blockade. MK-5890 reduced in an isotype-dependent and dose-dependent manner circulating, but not tumor-infiltrating T-cell numbers in these mouse models. In rhesus monkey and human patients, reduction in circulating T cells was transient and less pronounced than in mouse. MK-5890 induced transient elevation of chemokines MCP-1, MIP-1α, and MIP-1ß in the serum of mice, rhesus monkeys and patients with cancer. MK-5890 was well tolerated in rhesus monkeys and systemic exposure to MK-5890 was associated with CD27 occupancy at all doses. CONCLUSIONS: MK-5890 is a novel CD27 agonistic antibody with the potential to complement the activity of PD-1 checkpoint inhibition in cancer immunotherapy and is currently undergoing clinical evaluation.


Assuntos
Neoplasias , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Animais , Anticorpos Monoclonais/uso terapêutico , Contagem de Células , Epitopos , Humanos , Imunoterapia , Macaca mulatta , Camundongos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1
17.
Am J Pathol ; 192(10): 1379-1396, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35963463

RESUMO

Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis.


Assuntos
Carcinoma Hepatocelular , Hepatite C , Proteínas de Checkpoint Imunológico , Neoplasias Hepáticas , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Antivirais , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular , Hepacivirus , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Ligantes , Neoplasias Hepáticas/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno , Prognóstico , Resposta Viral Sustentada , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
18.
Eur J Immunol ; 52(10): 1630-1639, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35862268

RESUMO

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.


Assuntos
Subpopulações de Linfócitos B , Subpopulações de Linfócitos B/metabolismo , Separação Celular , Glicosilação , Humanos , Imunoglobulina D/metabolismo , Isotipos de Imunoglobulinas/metabolismo , Imunoglobulina M/metabolismo , Memória Imunológica/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
19.
Eur J Immunol ; 52(10): 1620-1629, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35856659

RESUMO

CD27/CD70 costimulation enhances T-cell survival, memory formation and Th1-cell differentiation and effector function. In addition to promoting Th1 responses, CD27 signaling has been shown to exert a negative regulatory role on IL-17 production, resulting in increased sensitivity of CD27 KO mice to EAE. By inducing EAE in full CD27 KO mice, and in a novel, T-cell specific CD27 KO mouse strain (CD4-Cre x CD27flox/flox ), we demonstrate herein that CD27 engagement by its natural ligand (CD70) suppresses IL-17 production in a cell autonomous fashion. We further show that CD27 engagement by an agonistic antibody given after EAE induction or at symptom onset similarly suppresses IL-17 production by activated CD4+ T cells infiltrating the inflamed CNS while IFN-γ production was unaffected, leading to an amelioration of inflammatory-related symptoms. These findings propose CD27 costimulation as a potential candidate for therapeutic manipulation to treat autoimmune and autoinflammatory diseases characterized by excessive IL-17 production.


Assuntos
Ligante CD27 , Encefalomielite Autoimune Experimental , Animais , Interleucina-17 , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Células Th1 , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral
20.
Cell Mol Immunol ; 19(7): 791-804, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35545662

RESUMO

Type 2 diabetes (T2D) is highly associated with obesity. However, the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder. Mucosal-associated invariant T (MAIT) cells, which are innate-like T cells that recognize bacterial metabolites, have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity. By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D, we found an elevation in CD27-negative (CD27-) MAIT cells producing a high level of IL-17 under T2D obese conditions, which could be positively correlated with impaired glucose metabolism in obese people. We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities. Specifically, accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17-producing CD27- MAIT cell expansion and could be associated with T2D risk in obese individuals. Overall, these results suggest that an aberrant gut microbiota-immune axis in obese people may drive or exacerbate T2D. Importantly, CD27- MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies. Our findings extend current knowledge regarding the clinical relevance of body mass index (BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.


Assuntos
Diabetes Mellitus Tipo 2 , Células T Invariantes Associadas à Mucosa , Bacteroides , Estudos Transversais , Glucose , Humanos , Interleucina-17 , Obesidade , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
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