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BACKGROUND: Evidence of the genetic interconnectedness between PD-1/PD-L1 and circulating biomarkers related to physiological and pathological processes is largely unclear. Understanding these genetic links is crucial for gaining insights into the underlying mechanisms and potential implications in cancer immunotherapy. METHODS: To shed light on potential roles of 90 circulating biomarkers in PD-1/PD-L1, we conducted a comprehensive Mendelian randomization (MR) analysis, leveraging genetic data from large-scale genome-wide association studies. RESULTS: Our results revealed negative associations between EN-RAGE and TRAIL-R2 with PD-1 levels. Additionally, we observed that PD-1 levels were positively associated with TRAIL, VEGF, and ANPEP, indicating their potential role in PD-1 upregulation. Furthermore, our analysis revealed causal associations between several circulating proteins and PD-L1 levels. Thrombomodulin, PSGL-1, TNFSF14, renin, follistatin, ß-NGF, KLK6, and MMP-7 demonstrated significant effects on PD-L1 regulation, suggesting their potential inhibitory role in immune checkpoint regulation. Eventually, we confirmed the potential roles of key genes involved in above circulating proteins in influencing the response to immunotherapy. CONCLUSIONS: Our findings provide valuable evidence of the genetic interconnectedness between PD-1/PD-L1 and circulating proteins related to physiological and pathological processes, shedding light on their potential roles in disease progression and therapeutic interventions.
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Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy.
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Extraparenchymal neurocysticercosis (EP-NC) is a chronic, potentially life-threatening disease that responds poorly to initial anthelmintic drug therapy. A depressed specific reactivity of peripheral lymphocytes and an increased level of specific Tregs accompanies EP-NC. The immune checkpoint pathway PD-1 and its ligand PD-L1 downregulates effector T cells, causing specific immune suppression in chronic diseases. This study explored whether their soluble forms, sPD-1/sPD-L1, are present in plasma among patients with EP-NC and if their levels could be associated with treatment response. A total of 21 patients with vesicular EP-NC and 22 healthy controls were included. Patients received standard treatment and were followed for six months to assess treatment response by assessing changes in cyst volume determined with 3D MRI. The presence of both sPD-1 and sPD-L1 was more frequently detected among patients with EP-NC than in healthy controls and had higher concentrations. Among patients, higher pre-treatment levels of both markers were associated with a poor treatment response, and the sensitivity and specificity of the sPD-1/sPD-L1 ratio for predicting any response to treatment were high. Our results are consistent with the presence of lymphocyte exhaustion and open new research perspectives to improve the prognosis of patients with this severe disease.
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BACKGROUND: Conflicting results about the effect of concomitant medications on immunotherapy in non-small cell lung cancer (NSCLC) were reported by many meta-analyses (MAs), and the certainty of evidence linking concomitant medications with immunotherapy efficacy has not been quantified, which may cause some evidence to be misinterpreted. METHODS: Four databases including Embase, Cochrane Library, PubMed, and Web of Science were searched from inception to January 2023 in English. Based on prospective or retrospective clinical controlled trials including immunotherapy with concomitant medications or not in NSCLC, quantitative MAs reporting the efficacy of immunotherapy with binary direct comparison and enough extractable data were collected. The methodological quality, reporting quality, and risk of bias of included MAs were evaluated respectively. New meta-analyses were conducted and their evidence certainty was classified as nonsignificant, weak, suggestive, highly suggestive, or convincing. RESULTS: Fifteen MAs with 5 medications were included. After being assessed by AMSTAR-2, PRISMA, and ROBIS, the major shortcomings were focused on the registration of protocol, literature retrieval or data extraction, implementation of sensitivity analysis or evidence certainty assessment, and incomplete reporting in the section of method and result. New pooled analyses indicated that antibiotics (HR = 1.545[1.318-1.811]), steroids (HR = 1.784[1.520-2.093]), proton pump inhibitors (PPIs) (HR = 1.303[1.048-1.621]) and opioids (HR = 1.910[1.213-3.006]) could shorten overall survival (OS) in patients with NSCLC receiving immunotherapy. Besides, antibiotics (HR = 1.285[1.129-1.462]) and steroids (HR = 1.613[1.315-1.979]) were harmful to progression-free survival (PFS) in these patients significantly. No negative effect was found in nonsteroidal anti-inflammatory drugs and the objective response rate of all medications. High-level evidence suggested that using PPIs before or after the initiation of immunotherapy and using steroids during the first-course immunotherapy could weaken the OS of patients with NSCLC. Meanwhile, the negative effects of antibiotics and opioids on OS or PFS were only supported by moderate or low-level evidence. CONCLUSIONS: The concurrent usage of PPIs or steroids adversely affects the survival of patients with NSCLC receiving immunotherapy. Future investigations are required to ascertain whether these adverse effects are primarily attributed to the comorbidities or the concurrent medications.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Antibacterianos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Esteroides/uso terapêutico , Metanálise como Assunto , Ensaios Clínicos como AssuntoRESUMO
OBJECTIVE: To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. METHODS: Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. RESULTS: Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. CONCLUSION: Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.
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Doença Trofoblástica Gestacional , Metotrexato , Gravidez , Feminino , Humanos , Dactinomicina/uso terapêutico , Brasil , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/epidemiologia , Doença Trofoblástica Gestacional/patologia , Imunoterapia , Estudos RetrospectivosRESUMO
BACKGROUND: A full understanding of the economic burden associated with treatment-related adverse events (AEs) can aid estimates of the incremental costs associated with incorporating new technologies and support cost-effective economic modeling in Brazil. In this context, the main objective of this work was to evaluate in a real-life database: (i) the direct medical cost of monitoring the occurrence of AEs (CMO); (ii) the direct medical cost of managing an identified AE (CMN); and (iii) the total direct medical cost of monitoring and managing AEs (TMC), in quarterly periods from 0 to 24 months of the monitoring of cancer patients who used a PD-1 inhibitor from the perspective of the supplementary health system in Brazil. METHODS: This study was conducted from the supplementary health system (SSS) perspective and followed the methodological guidelines related to cost-of-illness studies. A bottom-up (person-based) approach was used to assess the use of health resources to monitor and manage AEs during the use of PD-1 inhibitors, which made it possible to capture differences in the mean frequency of the use of health services with stratification results for different subgroups. As the Brazilian SSS is complex, asymmetric, and fragmented, this study used information from different sources. The methodology was divided into three parts: (i) Data Source: clinical management of AEs; (ii) Microcosting: management of the economic burden of AEs; (iii) Statistical analysis: stratification of results for different subgroups. RESULTS: Analysis of the economic burden of toxicity showed higher CMO costs than CMN in all the periods analyzed. In general, for every BRL 100 on average invested in the TMC of AEs, BRL 95 are used to monitor the occurrence of the AE and only BRL 5 to manage an identified AE. This work also showed that the sociodemographic characteristics of patients, the journey of oncological treatment, and the toxicity profile affect the economic burden related to AE. CONCLUSION: This study provided real-world evidence of the economic burden of AEs associated with the use of PD-1 inhibitors in Brazil. This work also made methodological contributions by evaluating the economic burden of AE of PD-1 inhibitors considering the kinetics of toxicity occurrence and categorizing the costs in terms of CMO, CMN and TMC.
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Estresse Financeiro , Inibidores de Checkpoint Imunológico , Humanos , Brasil , Programas Governamentais , Recursos em SaúdeRESUMO
Abstract Objective To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. Methods Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. Results Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. Conclusion Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.
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Abstract Background The defect of B cell self-tolerance and the continuous antigen presentation by T cells (TCs) mediated by autoreactive B cells (BCs) play a key role in the occurrence and development of systemic lupus erythematosus (SLE). PD-1/PD-L1 signaling axis negatively regulates the immune response of TCs after activation and maintains immune tolerance. However, the effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B/CD4+TCs in the peripheral blood of patients with SLE has not been studied in detail. Methods PD-1/PD-L1 and Ki-67 levels in peripheral blood (PB) of 50 SLE patients and 41 healthy controls (HCs) were detected through flow cytometry, and then the expression of PD-1+/−cells and PD-L1+/−cells Ki-67 was further analyzed. CD19+B/CD4+TCs were separated for cell culture and the supernatant was collected to determine proliferation and differentiation of TCs. IL-10 and IFN-γ secretion in the supernatant was also determined using ELISA. Results The PD-1, PD-L1, and Ki-67 levels on CD19+B/CD4+TCs in patients with SLE were higher than HCs. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ cells was higher than that of PD-L1− cells, and the proliferative activity of PD-1+ cells was higher than that of PD-1− cells. In the system co-culturing CD19+B/CD4+TCs from HCs/SLE patients, activated BCs promoted TCs proliferation and PD-L1 expression among TCs. Addition of anti-PD-L1 to co-culture system restored the proliferation of TCs, and inhibited IL-10/IFN-γ level. The addition of anti-PD-L1 to co-culture system also restored Tfh and downregulated Treg in HCs. Conclusions Axis of PD-1/PD-L1 on CD19+B/CD4+TCs in PB of SLE patients is abnormal, and cell proliferation is abnormal. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ and PD-1+ cells compared with PD-L1− and PD-1− cells in SLE patients, respectively. CD19+B/CD4+TCs in SLE patients can interact through PD-1/PD-L1.
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Despite progress in understanding the biology of adrenocortical carcinoma (ACC), treatment options have not dramatically changed in the last three decades, nor have we learned how to avoid some of its long-term side effects. Our goal was to improve the understanding of immune pathways that may include druggable targets to enhance immune responses of patients with ACC, focusing on immune evasion and the activation of immune cells against ACC. Our strategy was aimed at improving insight regarding gene expression without steroid interference. Using approaches based on high and low steroid phenotypes (HSP and LSP, respectively), we characterized immune pathways using The Cancer Genome Atlas (TCGA) ACC cohort data. Although previous studies have suggested that patients with ACC receive minimal benefit from immunotherapy, high expression of immune modulators was noted in patients with LSP, suggesting the activation of these biomarkers may be an important adjuvant therapy target after clearance of excess glucocorticoids. In addition, patients with LSP ACC had higher immune cell infiltration than patients with HSP ACC and other cancer subtypes. Our findings can be summarized as follows (1): we confirmed and improved the definition of two immune response pathways to ACC (HSP and LSP) based on in silico transcriptome analysis (2), we demonstrated the steroid profile should be considered, otherwise analyses of ACC immune characteristics can generate confounding results (3), among the overexpressed immunotherapy targets, we demonstrated that LSP was rich in PDCD1LG2 (PD-L2) and both HSP and LSP overexpressed CD276 (B7-H3), which was associated with resistance to anti-PD1 therapy and may have accounted for the modest results of previous clinical trials, and (4) identification of patients with LSP or HSP ACC can be used to help determine whether immunotherapy should be used. In conclusion, we highlighted the differences between LSP and HSP, drawing attention to potential therapeutic targets (CD276, PDCD1, and PDCD1LG2). Treatments to reduce immune evasion, as well as the use of other natural and pharmacological immune activators, should include prior pharmacological inhibition of steroidogenesis. Attempts to combine these with tumor cell proliferation inhibitors, if they do not affect cells of the immune system, may produce interesting results.
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Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Transcriptoma , Adolescente , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Proliferação de Células/fisiologia , Simulação por Computador , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Microambiente Tumoral , Adulto JovemRESUMO
In the last decade, the development of immune checkpoint inhibitors have revolutionized the treatment of patients with advanced renal cell carcinoma, with the potential for dramatic changes in the therapeutic landscape. Nivolumab, a monoclonal antibody inhibitor of transmem-brane programmed cell death protein 1 (PD-1), was approved as monotherapy in 2015 for advanced renal cell carcinoma in patients previously treated with an agent targeting vascular endothelial growth factor. In April 2018, the combination of nivolumab and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 inhibitor, was approved for patients with previously untreated intermediate- and poor-risk advanced renal cell carcinoma. Then, in 2019, combination therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-1 ligand, PD-L1) with axitinib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor) were also approved for use in all risk groups. This review pre-sents a brief historical review of the association between immunology and oncology; describes essential aspects of the mechanism of action of immune checkpoint inhibitors; discusses the current evidence regarding the clinical use of different immunotherapy regimens for the treatment of patients with renal cell carcinoma, both clear cell and other histological types; and provides general information on their adverse effects. The role of appropriate patient selection is analyzed to allow individualization of therapy and improve the already promising results. Finally, per-spectives on the future use of immune checkpoint inhibitors to treat renal cancer are discussed.
En la última década, el desarrollo de inhibidores de puntos de control o checkpoints inmunológicos, ha revolucionado el tratamiento de los pacientes con carcinoma de células renales avanzado avizorándose posibles cambios dramáticos en el escenario terapéutico. Nivolumab, un anticuerpo monoclonal inhibidor de la proteína transmembrana de muerte celular programada 1 (PD-1), se aprobó como monoterapia en 2015 para carcinoma de células renales avanzado en pacientes previamente tratados con algún agente dirigido al factor de crecimiento endotelial vascular. En abril de 2018, la combinación de nivolumab e ipilimumab, un inhibidor del CTLA-4, fue aprobado para pacientes con carcinoma de células renales avanzado de riesgo intermedio y riesgo desfavorable, previamente no tratados. Luego, en 2019, terapias combinadas que consisten en pembrolizumab (anti-PD-1) o avelumab (anti-ligando-PD-1, PD-L1) con axitinib (un inhibidor del receptor tirosina kinasa del factor de crecimiento endotelial vascular); también fueron aprobadas para su uso en todos los grupos de riesgo. En esta revisión se presenta una breve reseña histórica sobre la asociación entre la inmunología y la oncología; se describen aspectos básicos del mecanismo de acción de los inhibidores de puntos de control inmunológicos; se discute la evidencia actual relacionada con el uso clínico de los distintos esquemas de inmu-noterapia para el tratamiento de pacientes con carcinoma de células renales, tanto de células claras como de otros tipos histológicos; y se entrega información general sobre sus efectos adversos. Se analiza el rol de la adecuada selección de pacientes que permita una individualización de la terapia y, por ende, una mejora de los ya promisorios resultados. Por último, se discuten las perspectivas sobre el uso futuro de los inhibidores de puntos de control inmunológicos para el tratamiento del cáncer renal.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/terapia , Imunoterapia/métodos , Neoplasias Renais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento , Fator A de Crescimento do Endotélio VascularRESUMO
PURPOSE: Cytokines are vital pro-inflammatory factors and involved in tumor immune infiltration, and immune infiltration is closely related to PD-1/PD-L1 blockades immunotherapy. This study aims to explore the associations between cytokines and prognosis and also PD-1/PD-L1 expression in early lung adenocarcinoma, which is seldom reported. METHODS: 324 early lung adenocarcinoma patients with prior surgical resection were included and the associations between overall survival time and clinical factors and also cytokines including IL-1ß, IL-6 and TNF-α were analyzed by multivariate cox regression and Kaplan-Meier curve (log-rank test). Resected tumor samples were randomly obtained to detect the PD-1/PD-L1 expression by immunohistochemistry, and Chi square test was used for relations between cytokines and PD-1/PD-L1 expression. RESULTS: In this study group, 26.2% patients showed a high level of IL-1ß and patients with high IL-1ß level showed 19 months shortened mOS than those with normal IL-1 ß expression (mOS: 24.00, 95%CI 11.98-36.02 vs 43.00, 95% CI 37.37-48.63, p = 0.017). Among detected samples, the positive rate of PD-1 was 25.0% (13/52), and the positive rate of PD-L1 was 37.3% (19/52). The positive rate of PD-1 was 36.1% higher in high-IL-1 ß-level group as compared to normal-IL-1ß-level group (50.0% vs 13.9%, p = 0.012). No significant association was found between IL-1 ß and PD-L1 expression. CONCLUSION: High expression level of IL-1ß was correlated with poor prognosis and higher positive rate of PD-1 expression, which gave us insights into biomarkers of survival prediction and immunotherapy in lung adenocarcinoma. Further studies were still needed.
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Adenocarcinoma de Pulmão/metabolismo , Antígeno B7-H1/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Distribuição de Qui-Quadrado , Feminino , Humanos , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Prognóstico , Análise de Regressão , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Glioblastoma is the most malignant and lethal subtype of glioma. Despite progress in therapeutic approaches, issues with the tumor immune landscape persist. Multiple immunosuppression pathways coexist in the tumor microenvironment, which can determine tumor progression and therapy outcomes. Research in immune checkpoints, such as the PD-1/PD-L1 axis, has renewed the interest in immune-based cancer therapies due to their ability to prevent immunosuppression against tumors. However, PD-1/PD-L1 blockage is not completely effective, as some patients remain unresponsive to such treatment. The production of adenosine is a major obstacle for the efficacy of immune therapies and is a key source of innate or adaptive resistance. In general, adenosine promotes the pro-tumor immune response, dictates the profile of suppressive immune cells, modulates the release of anti-inflammatory cytokines, and induces the expression of alternative immune checkpoint molecules, such as PD-1, thus maintaining a loop of immunosuppression. In this context, this review aims to depict the complexity of the immunosuppression in glioma microenvironment. We primarily consider the PD-1/PD-L1 axis and adenosine pathway, which may be critical points of resistance and potential targets for tumor treatment strategies.
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Due to the clinical success of cancer immunotherapy, the design of PD-1/PD-L1 inhibitors has become an area of active research. To date, only five monoclonal antibodies are approved by FDA. Despite the great effort for the development of small molecules and peptides as inhibitors, only one of those has reached clinical trials. Pharmacophore models are a proven useful tool for drug design. The effectiveness of receptor-based pharmacophore modeling is limited due to the neglect of protein flexibility and desolvation effects. In the present application, we performed co-solvent molecular dynamics simulations of PD-L1 protein in order to obtain a pharmacophore model of PD-L1 immunecheckpoint protein. The analysis of probe molecules affinities by PD-L1 resulted in the identification of C'CFG beta strands as the zone with the highest convergence of hotspots, which corresponds to PD-1/PD-L1 interaction surface. The interactions maintained with PD-L1 residues varied from hydrophobic interactions to hydrogen bonds and salt bridges with critical residues for PD-1/PD-L1 binding (M115, A121, Y123, I54, Y56, E58, R125). The superposition of known inhibitors of PD-L1 as Peptide-57, BMS-1166 and high affinity PD-1(HAPD-1) allowed us to validate the pharmacophore model due to the good correlation with its features. The pharmacophore described herein can lead to the optimization and design of more selective and potent anti-cancer drugs.
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Antígeno B7-H1/química , Simulação de Dinâmica Molecular , Solventes/química , Cristalização , Preparações Farmacêuticas/química , Domínios ProteicosRESUMO
We have previously identified a human CD8+HLA-DR+ regulatory T cell subset with the ability to suppress proliferation of autologous PBMCs responder cells through cell contact and CTLA-4 co-inhibitory molecule. The present study characterizes the complete phenotype of CD8+HLA-DR+ Treg cells which showed great similarities with classical CD4+ cells expressing forkhead box P3 (FOXP3). The shared features included the expression of programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), C-C chemokine receptor type 4 and 5 (CCR4 and CCR5), low expression of CD127, and a memory and effector-like phenotype. CD8+HLA-DR+ Treg-induced suppression on CD8+ responder T cells was abrogated by an anti-PD1 neutralizing antibody. Anti-PD-1 did not abrogate the suppressor effect induced on responder CD4+ T cells. In addition, CD8+HLA-DR+ Treg induced a preferential death on responder CD8+ T cells. This effect was not reversed by PD-1 neutralization. After activation, most CD8+HLA-DR+ Treg acquire programmed death-ligand 1 (PD-L1) expression. Interestingly, PD-L1 may induce apoptosis through CD80 expressed on activated CD8+ responder T cells. After PBMCs stimulation, CD8+HLA-DR+ Treg cells showed an increased frequency of IFN-γ and TNFα positive cells and higher degranulation. These data strongly argue against CD8+HLA-DR+ Treg being exhausted cells. Overall, the data presented in this study indicate that CD8+HLA-DR+ Treg and CD4+FOXP3+ Treg share phenotypic and functional features, which may provide cues to similar involvements in the control of antitumor immune responses and autoimmunity.
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Apoptose/imunologia , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Antígenos HLA-DR/imunologia , Humanos , Interferon gama/imunologia , Masculino , Linfócitos T Reguladores/citologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Pregnancy-induced hypertension (PIH) causes significant maternal and fetal morbidity and mortality. A decreased number of regulatory T (Treg) cells is associated with the pathogenesis of PIH. The programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway is critical to normal pregnancy (NP) by promoting Treg cell development. However, the relationship between PD-1/PD-L1 and Treg differentiation in PIH has not been fully elucidated. In this study, venous blood was obtained from 20 NP and 58 PIH patients. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood. The levels of Treg-related cytokines (TGF-β, IL-10, and IL-35) in serum and PBMCs were measured by ELISA. The percentage of Treg cells in PBMCs was assessed by flow cytometry. The mRNA levels of Treg-specific transcription factor Foxp3 in PBMCs, and PD-1 and PD-L1 in Treg cells were detected by qRT-PCR. The protein levels of PD-1 and PD-L1 in Treg cells were evaluated by western blot. The serum levels of TGF-β, IL-10, IL-35, and Foxp3 mRNA expression and CD4+CD25+ Treg cell percentage in PBMCs were decreased in PIH. Furthermore, a significant increase of PD-1 in Treg cells was found in PIH compared with NP. In addition, PD-L1 Fc, an activator of PD-1/PD-L1 pathway, increased Treg cell percentage, enhanced Foxp3 mRNA expression, and elevated levels of TGF-β, IL-10, and IL-35 in PBMCs. However, anti-PD-L1 mAb exerted a reverse effect. These findings revealed that PD-L1 Fc had a favorable effect on Treg cell differentiation, indicating a potential therapeutic value of PD-1/PD-L1 pathway for PIH treatment.
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Humanos , Feminino , Gravidez , Leucócitos Mononucleares/química , Interleucinas/metabolismo , Interleucina-10/metabolismo , Apoptose , Hipertensão Induzida pela Gravidez/metabolismo , Antígeno B7-H1/metabolismo , Ensaio de Imunoadsorção Enzimática , Leucócitos Mononucleares/metabolismo , Estudos de Casos e Controles , Western Blotting , Fator de Crescimento Transformador beta/metabolismo , Linfócitos T Reguladores/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.
RESUMO
Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.