RESUMO
BACKGROUND: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively. METHODS: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers. RESULTS: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease). CONCLUSIONS: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated. TRIAL REGISTRATION NUMBER: NEON-1 (NCT04186637) and NEON-2 (NCT04920383).
Assuntos
Anticorpos Monoclonais Humanizados , Antígeno CTLA-4 , Neoplasias , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Masculino , Feminino , Neoplasias/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Adulto , Antígeno CTLA-4/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Idoso de 80 Anos ou mais , Antígenos CD28RESUMO
BACKGROUND: There is a need to identify vascular and geroscience-relevant markers and mediators that can physiologically link ageing to vascular disease. There is evidence of specific T cell subsets, all influenced by age, that exert positive and negative effects on vascular health. CD31+, termed angiogenic T cells, have been linked to vascular repair whereas CD28null, termed senescent T cells, display pro-inflammatory and cytotoxic effector functions. OBJECTIVE: This study sought to determine the combined influence of increasing age and frailty status on these circulating CD31+ and CD28null T cell subsets. METHODS: This cross-sectional study recruited four different cohorts of men and women; young (20-30 years, n=22), older (65-75 years, n=17), robust non-frail (76+ years, n=17), and frail (76+ years, n=15) adults. Frailty was determined using the Fried Frailty method. T cell subsets were determined by whole blood flow cytometry based on the expression of CD3, CD4, CD8, CD31 and CD28. Cognitive impairment (CI) was measured via the Montreal Cognitive Assessment test. RESULTS: Whether expressed as circulating counts or as a % of total T cells, there was a progressive decrease (p<0.05) in CD31+ T cells with increasing age but paradoxically higher values (p<0.05) in the frail compared to the robust non-frail group. These changes were similar in the CD4+ and CD8+ fractions. CD28null T cells were considerably higher (p<0.05) in the frail compared to the robust non-frail group, including in the CD8+ (47% vs 29%, p<0.05) and CD4+ (4% vs 1%, p<0.05) fractions. CD28null T cell percentage was also higher (p<0.05) in those with moderate CI compared to mild CI and normal function. CONCLUSION: CD8+CD28null T cells are considerably elevated in frailty and with cognitive impairment and may serve as a useful target for intervention. Currently, the utility of CD31+ T cells as an ageing biomarker may be confined to healthy ageing cohorts.
Assuntos
Envelhecimento , Fragilidade , Humanos , Masculino , Feminino , Idoso , Fragilidade/sangue , Fragilidade/imunologia , Estudos Transversais , Envelhecimento/fisiologia , Envelhecimento/imunologia , Envelhecimento/sangue , Adulto , Antígenos CD28/sangue , Molécula-1 de Adesão Celular Endotelial a Plaquetas/sangue , Senescência Celular , Subpopulações de Linfócitos T/imunologia , Adulto Jovem , Idoso de 80 Anos ou mais , Idoso Fragilizado , Biomarcadores/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/imunologia , Linfócitos T/imunologiaRESUMO
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.
Assuntos
Antígenos CD28 , Linfócitos T CD8-Positivos , Fator 1-alfa Nuclear de Hepatócito , Receptores CXCR6 , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Humanos , Antígenos CD28/metabolismo , Antígenos CD28/genética , Antígenos CD28/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Camundongos , Receptores CXCR6/metabolismo , Receptores CXCR6/genética , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/patologia , Análise de Célula Única/métodos , Transdução de Sinais , Microambiente Tumoral/imunologia , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Antígenos CD28 , Antígenos CD57 , Linfócitos T CD8-Positivos , Senescência Celular , Neoplasias de Cabeça e Pescoço , Humanos , Antígenos CD28/metabolismo , Antígenos CD57/metabolismo , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Senescência Celular/imunologia , Interferon gama/metabolismo , Adulto , Proliferação de Células , Idoso de 80 Anos ou maisRESUMO
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.
Assuntos
Antígeno B7-H1 , Linfócitos T CD4-Positivos , Comunicação Celular , Células Dendríticas , Ativação Linfocitária , Receptor de Morte Celular Programada 1 , Transdução de Sinais , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Ativação Linfocitária/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Comunicação Celular/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígeno B7-1/metabolismo , Antígeno B7-1/imunologia , Antígeno CTLA-4/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Linfócitos T Reguladores/imunologia , Antígenos CD28/metabolismo , Antígenos CD28/imunologiaRESUMO
BACKGROUND: Uremia-associated immunodeficiency, mainly characterized by T cell dysfunction, exists in patients on maintenance hemodialysis (MHD) and promotes systemic inflammation. However, T cell senescence, one of the causes of T cell dysfunction, has not been clearly revealed yet. In this cross-sectional research, we aimed to study the manifestation of T cell premature senescence in MHD patients and further investigate the associated clinical factors. METHODS: 76 MHD patients including 33 patients with cardiovascular diseases (CVD) and 28 patients with arteriovenous fistula (AVF) event history were enrolled in this study. Complementarity determining region 3 (CDR3) of T cell receptor (TCR) was analyzed by immune repertoire sequencing (IR-Seq). CD28- T cell subsets and expression of senescence marker p16 and p21 genes were detected by multicolor flow cytometry and RT-qPCR, respectively. RESULTS: MHD patients had significantly decreased TCR diversity (P < 0.001), increased CDR3 clone proliferation (P = 0.001) and a left-skewed CDR3 length distribution. The proportion of CD4 + CD28- T cells increased in MHD patients (P = 0.014) and showed a negative correlation with TCR diversity (P = 0.001). p16 but not p21 expression in T cells was up-regulated in MHD patients (P = 0.039). Patients with CVD exhibited increased expression of p16 and p21 genes (P = 0.010 and 0.004, respectively), and patients with AVF events showed further TCR diversity and evenness reduction (P = 0.002 and 0.017, respectively) compared to patients without the comorbidities. Moreover, age, average convection volume, total cholesterol, high-density lipoprotein cholesterol and transferrin saturation were associated with TCR diversity or CD4 + CD28- T cell proportion (P < 0.05). CONCLUSIONS: MHD patients undergo T cell premature senescence characterized by significant TCR diversity reduction and repertoire skew, as well as accumulation of the CD4 + CD28- subset and up-regulation of p16 gene. Patients with CVD or AVF events show higher level of immunosenescence. Furthermore, T cell senescence in MHD patients is associated with blood cholesterol and uremic toxin retention, suggesting potential intervention strategies in the future.
Assuntos
Senescência Celular , Receptores de Antígenos de Linfócitos T , Diálise Renal , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Estudos Transversais , Inibidor de Quinase Dependente de Ciclina p21/genética , Linfócitos T/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Antígenos CD28 , Uremia/imunologia , Regiões Determinantes de Complementaridade/genética , Adulto , Doenças Cardiovasculares/imunologia , Linfócitos T CD4-Positivos/imunologiaRESUMO
OBJECTIVE: To investigate the effect of CD8+ CD28- T cells on acute graft-versus-host disease(aGVHD) after haploidentical hematopoietic stem cell transplantation(haplo-HSCT). METHODS: The relationship between absolute count of CD8+ CD28- T cells and aGVHD in 60 patients with malignant hematological diseases was retrospectively analyzed after haplo-HSCT, and the differences in the incidence rate of chronic graft-versus host disease(cGVHD), infection and prognosis between different CD8+ CD28- T absolute cells count groups were compared. RESULTS: aGVHD occurred in 40 of 60 patients after haplo-HSCT, with an incidence rate of 66.67%. The median occurrence time of aGVHD was 32.5(20-100) days. At 30 days after the transplantation, the absolute count of CD8+ CD28- T cells of aGVHD group was significantly lower than that of non-aGVHD group (P =0.03). Thus the absolute count of CD8+ CD28- T cells at 30 days after transplantation can be used to predict the occurrence of aGVHD to some extent. At 30 days after transplantation, the incidence rate of aGVHD in the low cell count group (CD8+ CD28- T cells absolute count < 0.06/µl) was significantly higher than that in the high cell count group (CD8+ CD28- T cells absolute count ≥0.06/µl,P =0.011). Multivariate Cox regression analysis further confirmed that the absolute count of CD8+ CD28-T cells at 30 days after transplantation was an independent risk factor for aGVHD, and the risk of aGVHD in the low cell count group was 2.222 times higher than that in the high cell count group (P =0.015). The incidence of cGVHD, fungal infection, EBV infection and CMV infection were not significantly different between the two groups with different CD8+ CD28- T cells absolute count. The overall survival, non-recurrent mortality and relapse rates were not significantly different between different CD8+ CD28- T cells absolute count groups. CONCLUSION: Patients with delayed CD8+ CD28- T cells reconstitution after haplo-HSCT are more likely to develop aGVHD, and the absolute count of CD8+ CD28- T cells can be used to predict the incidence of aGVHD to some extent. The absolute count of CD8+ CD28- T cells after haplo-HSCT was not associated with cGVHD, fungal infection, EBV infection, and CMV infection, and was also not significantly associated with the prognosis after transplantation.
Assuntos
Antígenos CD28 , Linfócitos T CD8-Positivos , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos Retrospectivos , Prognóstico , Transplante Haploidêntico , Doença Aguda , Masculino , Feminino , AdultoRESUMO
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.
Assuntos
Traumatismos por Explosões , Lesões Encefálicas Traumáticas , Antígenos CD28 , Camundongos Endogâmicos C57BL , NF-kappa B , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Masculino , Lesões Encefálicas Traumáticas/metabolismo , Antígenos CD28/metabolismo , Transdução de Sinais/fisiologia , Traumatismos por Explosões/complicações , Traumatismos por Explosões/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Barreira Hematoencefálica/metabolismo , Traumatismos Torácicos/complicaçõesRESUMO
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.
Assuntos
Antígeno B7-1 , Antígeno B7-2 , Antígenos CD28 , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Camundongos , Antígeno B7-1/metabolismo , Antígeno B7-1/imunologia , Antígeno B7-2/metabolismo , Antígeno B7-2/imunologia , Camundongos Endogâmicos BALB C , Fatores de Transcrição Forkhead/metabolismo , Peptídeos/farmacologia , Peptídeos/imunologia , Ativação Linfocitária/imunologia , Interleucina-4/metabolismo , Interleucina-4/imunologia , Interleucina-13/metabolismo , Interleucina-13/imunologia , Ovalbumina/imunologia , Baço/imunologia , Baço/citologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/imunologiaRESUMO
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.
Assuntos
Líquido da Lavagem Broncoalveolar , Doenças Pulmonares Intersticiais , Subpopulações de Linfócitos T , Humanos , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Citocinas/metabolismo , Citocinas/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Citometria de Fluxo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Linfócitos T Citotóxicos/imunologiaRESUMO
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.
Assuntos
Adenosina Desaminase , Antígenos CD28 , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Dipeptidil Peptidase 4 , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígenos CD28/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/genética , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Masculino , Apirase/metabolismoAssuntos
Antígenos CD28 , Mieloma Múltiplo , Linfócitos T Reguladores , Humanos , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Linfócitos T Reguladores/imunologia , Prognóstico , Intervalo Livre de Progressão , Quimioterapia de Indução , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Taxa de Sobrevida , MasculinoRESUMO
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.
Assuntos
ADP-Ribosil Ciclase 1 , Mieloma Múltiplo , Linfócitos T , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/imunologia , ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Complexo CD3/metabolismo , Antígenos CD28/metabolismo , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Linhagem Celular Tumoral , RecidivaRESUMO
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.
Assuntos
COVID-19 , Interleucina-18 , Células Matadoras Naturais , Monócitos , Transdução de Sinais , Síndrome de Resposta Inflamatória Sistêmica , Receptor fas , Humanos , Interleucina-18/metabolismo , Criança , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptor fas/metabolismo , Receptor fas/genética , Monócitos/imunologia , Monócitos/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , COVID-19/imunologia , COVID-19/virologia , COVID-19/metabolismo , COVID-19/complicações , Inflamassomos/metabolismo , Inflamassomos/imunologia , SARS-CoV-2/imunologia , Adolescente , Masculino , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Feminino , Pré-Escolar , Análise de Célula Única , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD28/metabolismo , Ativação Linfocitária/imunologia , Receptores de Interleucina-18/metabolismo , Receptores de Interleucina-18/genética , Receptores de Interleucina-18/imunologiaAssuntos
ADP-Ribosil Ciclase 1 , Anticorpos Monoclonais Humanizados , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/metabolismo , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo CD3/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Antígenos CD28 , Idoso de 80 Anos ou mais , Masculino , Feminino , Anticorpos Biespecíficos/uso terapêutico , Glicoproteínas de MembranaRESUMO
Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.
Assuntos
Antígenos CD28 , Antígeno CTLA-4 , Cromatina , Regulação da Expressão Gênica , Humanos , Antígeno CTLA-4/genética , Antígenos CD28/genética , Cromatina/genética , Cromatina/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Sistemas CRISPR-CasRESUMO
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.
Assuntos
Antígenos CD19 , Antígenos CD28 , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral , Receptor de Morte Celular Programada 1 , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Humanos , Animais , Receptor de Morte Celular Programada 1/metabolismo , Antígenos CD28/metabolismo , Antígenos CD28/imunologia , Imunoterapia Adotiva/métodos , Antígenos CD19/imunologia , Linhagem Celular Tumoral , Feminino , Neoplasias/imunologia , Neoplasias/terapia , Masculino , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Pessoa de Meia-Idade , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , IdosoRESUMO
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.
Assuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Animais , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Camundongos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Antígenos B7/metabolismo , Antígenos B7/imunologia , Antígenos CD28/metabolismo , Antígenos CD28/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Análise da Randomização Mendeliana , Fenótipo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Receptores CCR2/genética , Linfócitos T CD8-Positivos/imunologia , Antígenos CD28/genéticaRESUMO
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.