RESUMEN
Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Inhibidores de Puntos de Control Inmunológico , Miocarditis , Femenino , Humanos , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Antígenos CD28/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Resultado Fatal , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Miocarditis/inducido químicamente , Ensayos Clínicos Fase I como AsuntoRESUMEN
CD8+ T cells must persist and function in diverse tumor microenvironments to exert their effects. Thus, understanding common underlying expression programs could better inform the next generation of immunotherapies. We apply a generalizable matrix factorization algorithm that recovers both shared and context-specific expression programs from diverse datasets to a single-cell RNA sequencing (scRNA-seq) compendium of 33,161 CD8+ T cells from 132 patients with seven human cancers. Our meta-single-cell analyses uncover a pan-cancer T cell dysfunction program that predicts clinical non-response to checkpoint blockade in melanoma and highlights CXCR6 as a pan-cancer marker of chronically activated T cells. Cxcr6 is trans-activated by AP-1 and repressed by TCF1. Using mouse models, we show that Cxcr6 deletion in CD8+ T cells increases apoptosis of PD1+TIM3+ cells, dampens CD28 signaling, and compromises tumor growth control. Our study uncovers a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity.
Asunto(s)
Antígenos CD28 , Linfocitos T CD8-positivos , Factor Nuclear 1-alfa del Hepatocito , Receptores CXCR6 , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Animales , Humanos , Antígenos CD28/metabolismo , Antígenos CD28/genética , Antígenos CD28/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Ratones , Receptores CXCR6/metabolismo , Receptores CXCR6/genética , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/patología , Análisis de la Célula Individual/métodos , Transducción de Señal , Microambiente Tumoral/inmunología , Ratones Endogámicos C57BLRESUMEN
Surface expression of programmed death-ligand 1 (PD-L1) is mainly observed on antigen presenting cells (APC) such as monocytes or dendritic cells (DCs). Our results showing a high expression of PD-L1 on human naïve CD4+ effector T-cells (TEFFs) and CD4+ regulatory T cells (TREGs) after activation with human DCs, allow us to propose a new role for PD-L1 and its ligands and their potential impact on new signaling pathways. Indeed, expression of PD-L1 on activated CD4+T cells could allow cis interaction with its ligands such as PD-1 and CD80, thus disrupting interactions with other signaling receptors, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or CD28, which interact with CD80. The ability to compete with hypothetical configuration modifications that may cause a change in affinity/avidity for the trans and cis interactions between these proteins expressed on T cells and/or DCs is discussed. As the study of cancer is strongly influenced by the role of the PD-L1/PD-1 pathway and CD4+T cells, new interactions, cis and/or trans, between TEFFs, TREGs and tumor cells are also proposed. The presence of PD-L1 on activated CD4+ T cells could influence the quality of the cytotoxic T lymphocyte response during priming to provide other help signals.
Asunto(s)
Antígeno B7-H1 , Linfocitos T CD4-Positivos , Comunicación Celular , Células Dendríticas , Activación de Linfocitos , Receptor de Muerte Celular Programada 1 , Transducción de Señal , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/inmunología , Activación de Linfocitos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Comunicación Celular/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Antígeno B7-1/metabolismo , Antígeno B7-1/inmunología , Antígeno CTLA-4/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Linfocitos T Reguladores/inmunología , Antígenos CD28/metabolismo , Antígenos CD28/inmunologíaRESUMEN
Improving cancer immunotherapy efficacy hinges on identifying key T-cell populations critical for tumor control and response to Immune Checkpoint Blockade (ICB). We have recently reported that while the co-expression of PD-1 and CD28 is associated with impaired functionality in peripheral blood, it significantly enhances T-cell fitness in the tumor site of non-small cell lung cancer (NSCLC) patients. To uncover the underlying mechanisms, we explored the role of CD26, a key player in T-cell activation through its interaction with adenosine deaminase (ADA), a crucial intra/extracellular enzyme able to neutralize local adenosine (ADO). We found that an autocrine ADA/CD26 axis enhances CD8+PD-1+CD28+ T-cell function, particularly within an immunosuppressive environment marked by CD39 expression. Then, we interrogated the TCGA and OAK datasets to gain insight into the prognostic/predictive potential of our findings. We identified a signature predicting overall survival (OS) in LUAD patients and response to atezolizumab in advanced LUAD cases. These findings suggest promising avenues for therapeutic intervention targeting the ADA/CD26 axis.
Asunto(s)
Adenosina Desaminasa , Antígenos CD28 , Linfocitos T CD8-positivos , Carcinoma de Pulmón de Células no Pequeñas , Dipeptidil Peptidasa 4 , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Receptor de Muerte Celular Programada 1 , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígenos CD28/metabolismo , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Dipeptidil Peptidasa 4/genética , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Masculino , Apirasa/metabolismoRESUMEN
T lymphocytes expressing CD57 and lacking costimulatory receptors CD27/CD28 have been reported to accumulate with aging, chronic infection, and cancer. These cells are described as senescent, with inability to proliferate but enhanced cytolytic and cytokine-producing capacity. However, robust functional studies on these cells taken directly from cancer patients are lacking. We isolated these T cells and their CD27/28+ counterparts from blood and tumor samples of 50 patients with previously untreated head and neck cancer. Functional studies confirmed that these cells have enhanced ability to degranulate and produce IFN-γ. They also retain the ability to proliferate, thus are not senescent. These data suggest that CD27/28-CD57+ CD8+ T cells are a subset of highly differentiated, CD45RA+ effector memory (TEMRA) cells with retained proliferative capacity. Patients with > 34% of these cells among CD8+ T cells in the blood had a higher rate of locoregional disease relapse, suggesting these cells may have prognostic significance.
Asunto(s)
Antígenos CD28 , Antígenos CD57 , Linfocitos T CD8-positivos , Senescencia Celular , Neoplasias de Cabeza y Cuello , Humanos , Antígenos CD28/metabolismo , Antígenos CD57/metabolismo , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/metabolismo , Masculino , Persona de Mediana Edad , Femenino , Anciano , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Senescencia Celular/inmunología , Interferón gamma/metabolismo , Adulto , Proliferación Celular , Anciano de 80 o más AñosRESUMEN
Mixed lymphocyte culture under the blockade of CD80/CD86-CD28 co-stimulation induces anergic (completely hyporesponsive) T cells with immune suppressive function (inducible suppressing T cells: iTS cells). Previously, iTS cell therapy has demonstrated outstanding benefits in clinical trials for organ transplantation. Here, we examined whether peptide antigen-specific iTS cells are inducible. DO 11.10 iTS cells were obtained from splenocytes of BALB/c DO 11.10 mice by stimulation with OVA peptide and antagonistic anti-CD80/CD86 mAbs. When DO 11.10 iTS or Foxp3- DO 11.10 iTS cells were stimulated with OVA, these cells produced IL-13, but not IL-4. DO 11.10 iTS cells decreased IL-4 and increased IL-13 production from OVA-stimulated naïve DO 11.10 splenocytes. When Foxp3+ DO 11.10 iTS cells were prepared, these cells significantly inhibited the production of IL-4 and IL-13 compared with freshly isolated Foxp3+ DO 11.10 T cells. Moreover, an increase in the population expressing OX40, ICOS, and 4-1BB suggested activation of Foxp3+ DO 11.10 iTS cells. Thus, blockade of CD80/CD86-CD28 co-stimulation during peptide antigen stimulation augments the inhibitory function of Foxp3+ regulatory T cells, and does not induce anergic Foxp3- conventional T cells. Peptide-specific Foxp3+ regulatory iTS cells could be useful for the treatment of allergic and autoimmune diseases without adverse effects.
Asunto(s)
Antígeno B7-1 , Antígeno B7-2 , Antígenos CD28 , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Ratones , Antígeno B7-1/metabolismo , Antígeno B7-1/inmunología , Antígeno B7-2/metabolismo , Antígeno B7-2/inmunología , Ratones Endogámicos BALB C , Factores de Transcripción Forkhead/metabolismo , Péptidos/farmacología , Péptidos/inmunología , Activación de Linfocitos/inmunología , Interleucina-4/metabolismo , Interleucina-4/inmunología , Interleucina-13/metabolismo , Interleucina-13/inmunología , Ovalbúmina/inmunología , Bazo/inmunología , Bazo/citología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/inmunologíaRESUMEN
In modern war or daily life, blast-induced traumatic brain injury (bTBI) is a growing health concern. Our previous studies demonstrated that inflammation was one of the main features of bTBI, and CD28-activated T cells play a central role in inflammation. However, the mechanism of CD28 in bTBI remains to be elucidated. In this study, traumatic brain injury model induced by chest blast exposure in male mice was established, and the mechanism of CD28 in bTBI was studied by elisa, immunofluorescence staining, flow cytometry analysis and western blot. After exposure to chest shock wave, the inflammatory factors IL-4, IL-6 and HMGB1 in serum were increased, and CD3+ T cells, CD4+ and CD8+ T cell subsets in the lung were activated. In addition, chest blast exposure resulted in impaired spatial learning and memory ability, disruption of the blood-brain barrier (BBB), and the expression of Tau, p-tau, S100ß and choline acetyltransferase were increased. The results indicated that genetic knockdown of CD28 could inhibit inflammatory cell infiltration, as well as the activation of CD3+ T cells, CD4+ and CD8+ T cell subsets in the lung, improve spatial learning and memory ability, and ameliorate BBB disruption and hippocampal neuron damage. Moreover, genetic knockdown of CD28 could reduce the expression of p-PI3K, p-AKT and NF-κB. In conclusion, chest blast exposure could lead to bTBI, and attenuate bTBI via the PI3K/AKT/NF-κB signaling pathway in male mice. This study provides new targets for the prevention and treatment of veterans with bTBI.
Asunto(s)
Traumatismos por Explosión , Lesiones Traumáticas del Encéfalo , Antígenos CD28 , Ratones Endogámicos C57BL , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Masculino , Lesiones Traumáticas del Encéfalo/metabolismo , Antígenos CD28/metabolismo , Transducción de Señal/fisiología , Traumatismos por Explosión/complicaciones , Traumatismos por Explosión/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Modelos Animales de Enfermedad , Barrera Hematoencefálica/metabolismo , Traumatismos Torácicos/complicacionesRESUMEN
The study aimed to investigate the expression profiles of transcription factors, cytokines, and co-stimulatory molecules in helper T (Th)-cell subsets within bronchoalveolar lavage (BAL) samples of patients with interstitial lung diseases (ILDs). Twenty ILDs patients were included in the study, comprising those with idiopathic pulmonary fibrosis (IPF) (n:8), autoimmune-related ILDs (auto-ILD) (n:4), and orphan diseases (O-ILD) (n:8), alongside five control subjects. Flow cytometry was employed to evaluate the Th to cytotoxic T cell (CTL) ratio in BAL fluid, while cytopathological examination assessed macrophages, lymphocytes, and neutrophils. Quantitative real-time polymerase chain reaction was utilized to investigate the expressions in Th1, Th2, Th17, and regulatory T (Treg) cells. Results revealed elevated Th cell to CTL ratios across all patient groups compared to controls. Furthermore, upregulation of Th1, Th2, Th17, and T-cell factors was observed in all patient groups compared to controls. Interestingly, upregulation of CD28 and downregulation of CTLA-4 and PD-1 gene expression were consistent across all ILDs groups, highlighting potential immune dysregulation. This study provides a comprehensive exploration of molecular immunological mechanisms in ILDs patients, underscoring the dominance of Th2 and Th17 responses and revealing novel findings regarding the dysregulation of CD28, CTLA-4, and PD-1 expressions in ILDs for the first time.
Asunto(s)
Líquido del Lavado Bronquioalveolar , Enfermedades Pulmonares Intersticiales , Subgrupos de Linfocitos T , Humanos , Enfermedades Pulmonares Intersticiales/inmunología , Enfermedades Pulmonares Intersticiales/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto , Citocinas/metabolismo , Citocinas/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Citometría de Flujo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Linfocitos T Citotóxicos/inmunologíaRESUMEN
BACKGROUND: For many years it has been postulated that the immune system controls the progress of multiple myeloma (MM). However, the phenotypes of T cells in MM remain to be elucidated. In this study, we compared the phenotypes of T cells, which were obtained from the peripheral blood, in MM patients with those in healthy donors (HD). The expression of CCR7, CD57, CD28, HLA-DR, CD38, CD45RA, and CD45RO were assessed on T cells from MM patients and HDs using multicolor flow cytometry (MFC). METHODS: For this study, 17 newly diagnosed MM patients were selected, and 20 healthy people were selected as a control group. MFC was used to detect the markers on T cells. RESULTS: We detected significant increases in the expression levels of HLA-DR, CD38, and CD57on CD8+ T cells, significant decreases in the expression levels of CD28 and CD45RA on CD8+ T cells, and a decrease of CD4+ effec-tor T cells in MM patients, compared to the HD group. CONCLUSIONS: Our study shows that the accumulation of peripheral CD8+CD57+T cells, CD8+CD38high T cells, and CD8+HLA-DR+CD38high T cells is reflective of an ongoing antitumor T cell response and a progressive immune dysfunction in MM. During chemotherapy, the recovery of immune function can be monitored by detecting the proportion of activated molecules of T lymphocytes.
Asunto(s)
ADP-Ribosil Ciclasa 1 , Antígenos CD28 , Citometría de Flujo , Antígenos HLA-DR , Antígenos Comunes de Leucocito , Mieloma Múltiple , Femenino , Humanos , Masculino , ADP-Ribosil Ciclasa 1/metabolismo , Estudios de Casos y Controles , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Antígenos CD57/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Antígenos HLA-DR/sangre , Inmunofenotipificación/métodos , Antígenos Comunes de Leucocito/metabolismo , Glicoproteínas de Membrana/inmunología , Mieloma Múltiple/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
The length of 3' untranslated regions (3'UTR) is highly regulated during many transitions in cell state, including T cell activation, through the process of alternative polyadenylation (APA). However, the regulatory mechanisms and functional consequences of APA remain largely unexplored. Here we present a detailed analysis of the temporal and condition-specific regulation of APA following activation of primary human CD4+ T cells. We find that global APA changes are regulated temporally and CD28 costimulatory signals enhance a subset of these changes. Most APA changes upon T cell activation involve 3'UTR shortening, although a set of genes enriched for function in the mTOR pathway exhibit 3'UTR lengthening. While upregulation of the core polyadenylation machinery likely induces 3'UTR shortening following prolonged T cell stimulation; a significant program of APA changes occur prior to cellular proliferation or upregulation of the APA machinery. Motif analysis suggests that at least a subset of these early changes in APA are driven by upregulation of RBM3, an RNA-binding protein which competes with the APA machinery for binding. Together this work expands our understanding of the impact and mechanisms of APA in response to T cell activation and suggests new mechanisms by which APA may be regulated.
Asunto(s)
Regiones no Traducidas 3' , Activación de Linfocitos , Poliadenilación , Humanos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Regulación de la Expresión Génica , Transducción de Señal , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Antígenos CD28/metabolismo , Antígenos CD28/genética , Linfocitos T/metabolismo , Linfocitos T/inmunologíaRESUMEN
Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson's r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-ß (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-ß inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.
Asunto(s)
ADP-Ribosil Ciclasa 1 , Mieloma Múltiple , Linfocitos T , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Mieloma Múltiple/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacos , Complejo CD3/metabolismo , Antígenos CD28/metabolismo , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Línea Celular Tumoral , RecurrenciaRESUMEN
Chimeric antigen receptor (CAR)-T cell therapy shows impressive efficacy treating hematologic malignancies but requires further optimization in solid tumors. Here, we developed a TMIGD2 optimized potent/persistent (TOP) CAR that incorporated the costimulatory domain of TMIGD2, a T and NK cell costimulator, and monoclonal antibodies targeting the IgV domain of B7-H3, an immune checkpoint expressed on solid tumors and tumor vasculature. Comparing second- and third-generation B7-H3 CARs containing TMIGD2, CD28, and/or 4-1BB costimulatory domains revealed superior antitumor responses in B7-H3.TMIGD2 and B7-H3.CD28.4-1BB CAR-T cells in vitro. Comparing these two constructs using in vivo orthotopic human cancer models demonstrated that B7-H3.TMIGD2 CAR-T cells had equivalent or superior antitumor activity, survival, expansion, and persistence. Mechanistically, B7-H3.TMIGD2 CAR-T cells maintained mitochondrial metabolism; produced less cytokines; and established fewer exhausted cells, more central memory cells, and a larger CD8/CD4 T cell ratio. These studies demonstrate that the TOP CAR with TMIGD2 costimulation offered distinct benefits from CD28.41BB costimulation and is effective against solid tumors.
Asunto(s)
Inmunoterapia Adoptiva , Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Animales , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia Adoptiva/métodos , Ratones , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Antígenos B7/metabolismo , Antígenos B7/inmunología , Antígenos CD28/metabolismo , Antígenos CD28/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Multisystem inflammatory syndrome in children is a post-infectious presentation SARS-CoV-2 associated with expansion of the T cell receptor Vß21.3+ T-cell subgroup. Here we apply muti-single cell omics to compare the inflammatory process in children with acute respiratory COVID-19 and those presenting with non SARS-CoV-2 infections in children. Here we show that in Multi-Inflammatory Syndrome in Children (MIS-C), the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleuking 18 receptor expression. Additionally, TCR Vß21.3+ CD4+ T-cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells, with increased expression of the co-stimulation receptors ICOS, CD28 and interleukin 18 receptor. We observe no functional evidence for NLRP3 inflammasome pathway overactivation, though MIS-C monocytes show elevated active caspase 8. This, coupled with raised IL18 mRNA expression in CD16- NK cells on single cell RNA sequencing analysis, suggests interleukin 18 and CD95 signalling may trigger activation of TCR Vß21.3+ T-cells in MIS-C, driven by increased IL-18 production from activated monocytes and CD16- Natural Killer cells.
Asunto(s)
COVID-19 , Interleucina-18 , Células Asesinas Naturales , Monocitos , Transducción de Señal , Síndrome de Respuesta Inflamatoria Sistémica , Receptor fas , Humanos , Interleucina-18/metabolismo , Niño , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Receptor fas/metabolismo , Receptor fas/genética , Monocitos/inmunología , Monocitos/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , COVID-19/inmunología , COVID-19/virología , COVID-19/metabolismo , COVID-19/complicaciones , Inflamasomas/metabolismo , Inflamasomas/inmunología , SARS-CoV-2/inmunología , Adolescente , Masculino , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Femenino , Preescolar , Análisis de la Célula Individual , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Antígenos CD28/metabolismo , Activación de Linfocitos/inmunología , Receptores de Interleucina-18/metabolismo , Receptores de Interleucina-18/genética , Receptores de Interleucina-18/inmunologíaRESUMEN
OBJECTIVES: γδ T-lymphocytes play a role in angiotensin II (AngII)-induced hypertension, vascular injury and T-cell infiltration in perivascular adipose tissue (PVAT) in mice. Mesenteric arteries of hypertensive mice and subcutaneous arteries from obese humans present similar remodeling. We hypothesized that γδ T-cell subtypes in mesenteric vessels with PVAT (MV/PVAT) from hypertensive mice and subcutaneous adipose tissue (SAT) from obese humans, who are prone to develop hypertension, would be similar. METHODS: Mice were infused with AngII for 14âdays. MV/PVAT T-cells were used for single-cell RNA-sequencing (scRNA-seq). scRNA-seq data (GSE155960) of SAT CD45 + cells from three lean and three obese women were downloaded from the Gene Expression Omnibus database. RESULTS: δ T-cell subclustering identified six δ T-cell subtypes. AngII increased T-cell receptor δ variable 4 ( Trdv4 ) + γδ T-effector memory cells and Cd28high δ T EM -cells, changes confirmed by flow cytometry. δ T-cell subclustering identified nine δ T-cell subtypes in human SAT. CD28 expressing δ T-cell subclustering demonstrated similar δ T-cell subpopulations in murine MV/PVAT and human SAT. Cd28+ γδ NKT EM and Cd28high δ T EM -cells increased in MV/PVAT from hypertensive mice and CD28high δ T EM -cells in SAT from obese women compared to the lean women. CONCLUSION: Similar CD28 + δ T-cells were identified in murine MV/PVAT and human SAT. CD28 high δ T EM -cells increased in MV/PVAT in hypertensive mice and in SAT from humans with obesity, a prehypertensive condition. CD28 + δ T-lymphocytes could have a pathogenic role in human hypertension associated with obesity, and could be a potential target for therapy.
Asunto(s)
Antígenos CD28 , Hipertensión , Obesidad , Grasa Subcutánea , Animales , Humanos , Hipertensión/inmunología , Hipertensión/metabolismo , Ratones , Grasa Subcutánea/metabolismo , Antígenos CD28/metabolismo , Femenino , Masculino , Angiotensina II , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Tejido Adiposo/metabolismoRESUMEN
The limited expansion ability and functional inactivation of T cells within the solid tumor microenvironment are major problems faced during in the application of using tumor-infiltrating lymphocytes (TILs) in vivo. We sought to determine whether TILs carrying a PD-1-CD28-enhanced receptor and CD19 CAR could overcome this limitation and mediate tumor regression. First, anti-tumor effects of PD-1-CD28-enhanced receptor or CD19 CAR modified NY-ESO-1-TCR-T cells to mimic the TILs function (hereafter "PD-1-CD28-TCR-T" or "CD19 CAR-TCR-T" cells, respectively) were tested using the NY-ESO-1 over-expressed tumor cell line in vitro and in a tumor-bearing model. Furthermore, the safety and anti-tumor ability of S-TILs (TILs modified through transduction with a plasmid encoding the PD-1-CD28-T2A-CD19 CAR) were evaluated in vivo. PD-1-CD28-TCR-T cells showed a formidable anti-tumor ability that was not subject to PD-1/PD-L1 signaling in vivo. CD19 CAR-TCR-T cells stimulated with CD19+ B cells exhibited powerful expansion and anti-tumor abilities both in vitro and in vivo. Three patients with refractory solid tumors received S-TILs infusion. No treatment-related mortality was observed, and none of the patients experienced serious side effects. One patient with melanoma achieved a partial response, and two patients with colon or kidney cancer achieved long-term stable disease following S-TILs therapy. To the best of our knowledge, this is the first study describing the safety and efficacy of the adoptive transfer of autologous S-TILs to control disease in patients with advanced cancers, suggesting that S-TILs may be a promising alternative therapy for cancer.
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Antígenos CD19 , Antígenos CD28 , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor , Receptor de Muerte Celular Programada 1 , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Humanos , Animales , Receptor de Muerte Celular Programada 1/metabolismo , Antígenos CD28/metabolismo , Antígenos CD28/inmunología , Inmunoterapia Adoptiva/métodos , Antígenos CD19/inmunología , Línea Celular Tumoral , Femenino , Neoplasias/inmunología , Neoplasias/terapia , Masculino , Ratones , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Persona de Mediana Edad , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , AncianoRESUMEN
Zinc is an essential trace element that plays a crucial role in T cell immunity. During T cell activation, zinc is not only structurally important, but zinc signals can also act as a second messenger. This research investigates zinc signals in T cell activation and their function in T helper cell 1 differentiation. For this purpose, peripheral blood mononuclear cells were activated via the T cell receptor-CD3 complex, and via CD28 as a costimulatory signal. Fast and long-term changes in intracellular zinc and calcium were monitored by flow cytometry. Further, interferon (IFN)-γ was analyzed to investigate the differentiation into T helper 1 cells. We show that fast zinc fluxes are induced via CD3. Also, the intracellular zinc concentration dramatically increases 72 h after anti-CD3 and anti-CD28 stimulation, which goes along with the high release of IFN-γ. Interestingly, we found that zinc signals can function as a costimulatory signal for T helper cell 1 differentiation when T cells are activated only via CD3. These results demonstrate the importance of zinc signaling alongside calcium signaling in T cell differentiation.
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Antígenos CD28 , Diferenciación Celular , Interferón gamma , Activación de Linfocitos , Piridinas , Tionas , Zinc , Humanos , Calcio/metabolismo , Antígenos CD28/agonistas , Antígenos CD28/metabolismo , Complejo CD3/metabolismo , Diferenciación Celular/efectos de los fármacos , Interferón gamma/metabolismo , Ionóforos/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Transducción de Señal/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/efectos de los fármacos , Zinc/metabolismo , Zinc/farmacología , Piridinas/química , Piridinas/farmacología , Tionas/química , Tionas/farmacologíaRESUMEN
BACKGROUND: The contradictory role of CD8 + CD28- T cells in tumour immunity has been reported, while their biological and clinical significance in HER2-positive metastatic breast cancer (MBC) is still unknown. METHODS: HER2-positive MBC patients with no prior therapy in the metastatic setting were retrospectively recruited at two medical centres. Peripheral CD8 + CD28- T cells (pTCD8+CD28-) were detected at baseline and following therapeutic intervals. Progression-free survival (PFS) was compared according to pTCD8+CD28- levels. The molecular features of pTCD8+CD28- and its correlation with tumour immunity were also investigated. RESULTS: A total of 252 patients were enrolled, and the median follow-up time was 29.6 months. pTCD8+CD28- high at baseline has prolonged PFS compared to pTCD8+CD28- low (P = 0.001). Patients who maintained pTCD8+CD28- high had a longer PFS than those who kept pTCD8+CD28- low (P < 0.001). The enhanced pTCD8+CD28- level also indicates a longer PFS compared to pTCD8+CD28- low (P = 0.025). Here, pTCD8+CD28- was demonstrated as an antigen-experienced effector T cell. Higher IL-2 level (P = 0.034) and lower TGF-ß level (P = 0.016) in the serum and highly infiltrated CD8 + CD28- T cells (P = 0.037) were also connected to pTCD8+CD28- high. CONCLUSIONS: High pTCD8+CD28- level is associated with a favourable tumour immunity and a better PFS of HER2-targeting therapy in MBC patients.
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Neoplasias de la Mama , Antígenos CD28 , Linfocitos T CD8-positivos , Receptor ErbB-2 , Adulto , Femenino , Humanos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Antígenos CD28/metabolismo , Linfocitos T CD8-positivos/inmunología , Metástasis de la Neoplasia , Supervivencia sin Progresión , Receptor ErbB-2/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND AIMS: Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain. METHODS: Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet lysate (HPL)-supplemented medium. RESULTS: We found that HPL supported greater expansion of CAR-Vδ2 T cells with comparable in vitro cytotoxicity and cytokine secretion to FBS-expanded CAR-Vδ2 T cells. HPL-expanded CAR-Vδ2 T cells showed enhanced in vivo anti-tumor activity with longer T-cell persistence compared with FBS counterparts, with 4-1BB costimulated CAR showing the greatest activity. Mechanistically, HPL-expanded CAR Vδ2 T cells exhibited reduced apoptosis and senescence transcriptional pathways compared to FBS-expanded CAR-Vδ2 T cells and increased telomerase activity. CONCLUSIONS: This study supports enhancement of therapeutic potency of CAR-Vδ2 T cells through a manufacturing improvement.
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Apoptosis , Plaquetas , Senescencia Celular , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Animales , Inmunoterapia Adoptiva/métodos , Ratones , Plaquetas/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Línea Celular Tumoral , Antígenos CD28/metabolismo , Antígenos CD28/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
CD28null T cells, an atypical subset characterized by the loss of CD28 costimulatory molecule expression, exhibit functional variants and progressively expand with age. Moreover, T cells with these phenotypes are found in both typical and atypical humoral immune responses. Consequently, they accumulate during infectious diseases, autoimmune disorders, cardiovascular conditions, and neurodegenerative ailments. To provide an in-depth review of the current knowledge regarding CD28null T cells, we specifically focus on their phenotypic and functional characteristics as well as their physiological roles in aging and diseases. While uncertainties regarding the clinical utility remains, we will review the following two crucial research perspectives to explore clinical translational applications of the research on this specific T cell subset: 1) addressing the potential utility of CD28null T cells as immunological markers for prognosis and adverse outcomes in both aging and disease, and 2) speculating on the potential of targeting CD28null T cells as an interventional strategy for preventing or delaying immune aging processes and disease progression.
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Enfermedades Autoinmunes , Antígenos CD28 , Humanos , Antígenos CD28/metabolismo , Envejecimiento , Subgrupos de Linfocitos T , Enfermedades Autoinmunes/metabolismo , Biología , Linfocitos T CD4-PositivosRESUMEN
Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4+ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 risk allele accelerate T cell differentiation into CXCR5-PD-1high Tph cells producing IL-21 and CXCL13. Thus, mechanistic dissection of a functional non-coding variant in human autoimmunity discloses a previously undefined pathway through which ICOS regulates Tph development and abundance.