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1.
Chin J Dent Res ; 23(2): 109-117, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32548602

RESUMO

OBJECTIVE: To understand the immune molecular landscapes of the two major costimulatory and coinhibitory pathways (B7 and TNFR families) in oral squamous cell carcinoma. METHODS: The B7 family members (CD80, CD86, CD274, ICOSLG, CD276, VTCN1, NCR3LG1, HHLA2 and PDCD1LG2) and TNFR family members (TNFSF4, CD40, CD70, TNFSF9, TNFRSF14 and TNFSF18) were used to analyse the costimulatory and coinhibitory pathway alterations in oral squamous cell carcinoma. The online tools UCSC Xena and cBioPortal were used to derive oral squamous cell carcinoma patients' clinical parameters, mRNA levels, mutations, DNA copy number alterations and methylation levels. The correlations between mRNA levels and methylation levels were determined using Spearman's correlation analysis. A Kaplan-Meier survival analysis was performed to examine the relationships between mRNA expression levels and overall survival. RESULTS: Compared with normal oral epithelial tissues, approximately 23.1% of patients showed upregulation of B7 expression and 15.3% showed upregulation of TNFR expression in oral squamous cell carcinoma, with CD274 (PD-L1) upregulation being the most common alteration. Mutations and copy number alterations were shown to have little effect on B7 and TNFR expression. The mRNA levels of B7 and TNFR genes were negatively correlated with their methylation levels. Furthermore, oral squamous cell carcinoma patients with high expression levels of CD274 showed poor overall survival, while those with high expression levels of CD276 or HHLA2 showed good clinical outcomes. CONCLUSION: This study elucidated the molecular landscapes of the B7 and TNFR genes in oral squamous cell carcinoma, which could provide a novel strategy for clinical therapy.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Antígenos B7 , Humanos
2.
Cancer Immunol Immunother ; 69(8): 1437-1446, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32266446

RESUMO

V-domain Ig suppressor of T cell activation (VISTA) is a novel immune checkpoint that is an emerging target for cancer immunotherapy. This study aimed to investigate the expression of VISTA and its association with clinicopathologic parameters as well as with the key immune markers including programmed cell death-1 (PD-1) and PD-1 ligand-1 (PD-L1) in invasive ductal carcinoma (IDC) of the breast [corrected]. Immunohistochemistry was used to detect VISTA, PD-1, PD-L1, and CD8 in tissue microarrays from 919 patients with IDC (N = 341 in the exploratory cohort and = 578 in the validation cohort). VISTA was expressed on the immune cells of 29.1% (267/919) of the samples and on the tumor cells of 8.2% (75/919). VISTA was more frequently expressed in samples that were estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor 2-positive, poorly differentiated, human epidermal growth factor receptor 2-enriched, and consisting of basal-like tumors. VISTA on immune cells correlated with PD-1, PD-L1, stromal CD8, and tumor-infiltrating lymphocyte expression and was an independent prognostic factor for improved relapse-free and disease-specific survival in patients with estrogen receptor-negative, progesterone receptor-negative, and basal-like IDC. These findings support therapeutic strategies that modulate VISTA expression, perhaps in combination with PD-1/PD-L1 blockade, in human breast cancer immunotherapy.


Assuntos
Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
3.
Clin Exp Immunol ; 200(1): 12-21, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31901178

RESUMO

CD28H and B7-H5 have been identified as receptor-ligand pairs in the B7/CD28 family, and have co-stimulatory activity in immune cells. Here, we have systematically reviewed the research reports concerning the CD28H/B7-H5 pathway. It was found that CD28H is mainly expressed in T cells and natural killer (NK) cells with naive and poorly differentiated properties, and repeated antigen stimulation leads to permanent loss of CD28H. In tumors, CD28H is mainly expressed in tissue-resident memory (TRM ) lymphocyte T cells, which is associated with improved tumor prognosis. B7-H5 is a ligand for CD28H and is widely expressed in tumor cells. B7-H5 expression is closely related to the prognosis of the tumor. Studies have shown that high expression of B7-H5 in tumor is related to a worse prognosis for lung cancer, osteosarcoma, oral squamous cell carcinoma (OSCC), breast carcinoma, human clear cell renal cell carcinoma (ccRCC), intrahepatic cholangiocarcinoma (ICC), bladder urothelial carcinoma (BUC) and colorectal cancer (CRC), but is associated with a better prognosis for pancreatic ductal adenocarcinoma (PDAC) and glioma. Controversial views exist in studies on gastric cancer prognosis.


Assuntos
Antígenos B7/imunologia , Antígenos CD28/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Células Th1/imunologia , Antígenos B7/genética , Antígenos B7/metabolismo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Células Matadoras Naturais/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Linfócitos T/metabolismo , Células Th1/metabolismo
4.
Science ; 367(6475)2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31949051

RESUMO

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.


Assuntos
Antígenos B7/fisiologia , Proteínas de Membrana/fisiologia , Tolerância Periférica/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais , Antígenos B7/genética , Ativação Linfocitária , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tolerância Periférica/genética , Receptores de Antígenos de Linfócitos T/fisiologia
5.
Cancer Immunol Immunother ; 69(4): 523-533, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31960110

RESUMO

The outcome in esophageal adenocarcinoma (EAC) is still poor with only 20% of patients in Western populations surviving for more than 5 years. Almost nothing is known about the precise composition of immune cells and their gene expression profiles in primary resected EACs and also nothing compared to neoadjuvant treated EACs. This study analyzes and compares immune profiles of primary resected and neoadjuvant treated esophageal adenocarcinoma and unravels possible targets for immunotherapy. We analyzed 47 EAC in total considering a set of 30 primary treatment-naive EACs and 17 neoadjuvant pretreated (12 × CROSS, 5 × FLOT) using the Nanostring's panel-based gene expression platform including 770 genes being important in malignant tumors and their immune micromileu. Most of the significantly altered genes are involved in the regulation of immune responses, T-and B cell functions as well as antigen processing. Chemokine-receptor axes like the CXCL9, -10,-11/CXCR3- are prominent in esophageal adenocarcinoma with a fold change of up to 9.5 promoting cancer cell proliferation and metastasis. ARG1, as a regulator of T-cell fate is sixfold down-regulated in untreated primary esophageal tumors. The influence of the currently used neoadjuvant treatment revealed a down-regulation of nearly all important checkpoint markers and inflammatory related genes in the local microenvironment. We found a higher expression of checkpoint markers like LAG3, TIM3, CTLA4 and CD276 in comparison to PD-L1/PD-1 supporting clinical trials analyzing the efficacy of a combination of different checkpoint inhibitors in EACs. We found an up-regulation of CD38 or LILRB1 as examples of additional immune escape mechanism.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/terapia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Antígenos B7/genética , Antígenos B7/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Quimiorradioterapia/métodos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/imunologia , Esofagectomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Imunológica , Terapia Neoadjuvante , Linfócitos T/imunologia , Linfócitos T/metabolismo
6.
J Clin Pathol ; 73(4): 197-203, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31672704

RESUMO

AIMS: Peripheral T cell lymphomas represent approximately 10%-15% of non-Hodgkin lymphomas and are characterised by an aggressive clinical courses and poor outcomes. Ligands provided by constituents of the tumour microenvironment engage receptors expressed by malignant T cells, promoting tumour growth and chemotherapy resistance. In addition to stimulatory receptors that promote the growth and survival of malignant T cells, recent studies suggest that homologous inhibitory receptors may have an opposing effect and function as tumour suppressors. For example, recent data suggest that programmed cell death 1 blockade may lead to increased lymphoma growth. Therefore, the identification of alternative checkpoint receptors in T cell lymphoproliferative neoplasms is an important and clinically relevant question. METHODS: The checkpoint receptors T cell immunoglobulin-3 (TIM-3), V-domain Ig-containing suppressor of T cell activation (VISTA) and lymphocyte-activation gene 3 (LAG-3) play fundamental roles in peripheral tolerance, and their ligands are exploited by many solid tumours to evade host immunity. However, their expression in T cell lymphoproliferative neoplasms has not been evaluated. In this study, we evaluated the expression of TIM-3, VISTA and LAG-3 in a cohort of peripheral T cell lymphomas cases by immunohistochemistry and flow cytometric analysis. RESULTS: Our results demonstrate that TIM-3, VISTA and LAG-3 expression is rarely identified within a large cohort of T cell lymphomas and its tumour microenvironment. CONCLUSIONS: Our data suggest that immune-regulatory roles for TIM-3, VISTA and LAG-3 may be predominant in lymphomas subsets different than the ones analysed in the current study. However, a potential role for these checkpoint receptors as tumour suppressors in T cell lymphomas remains to be elucidated.


Assuntos
Antígenos CD/metabolismo , Antígenos B7/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Linfoma de Células T Periférico/metabolismo , Adulto , Humanos , Imuno-Histoquímica , Masculino
7.
World Neurosurg ; 135: e12-e18, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31629137

RESUMO

BACKGROUND: The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. So far, little is known about the clinical significance of B7-H3 expression in meningiomas. We conducted this study to address this issue in a cohort of 242 patients from a single institution. METHODS: Expression profiles of immune checkpoint proteins (programmed death-ligand 1, B7-H3, lymphocyte activation gene-3, programmed death 1, and V-domain Ig suppressor of T cell activation) were explored by immunohistochemistry in a meningioma test cohort (n = 8). Role of B7-H3 expression was further assessed in an expanded patient cohort (n = 234) using immunohistochemical tissue microarray analysis. RESULTS: B7-H3 expression was significantly greater than all immune checkpoint proteins studied in the tested cohort. B7-H3 was detected with different degrees in all meningioma specimens, predominantly on tumor cell membranes and in cytoplasm. Tumors were classified as B7-H3 high or low group depending on immunohistochemistry histoscore (median histoscore 111.06; range, 7.313-212.008). B7-H3 expression was statistically correlated with patient sex (P = 0.0297), tumor histopathologic subtypes (P = 0.0262), and radiotherapy after surgery (P = 0.0028). However, no significant differences were observed in patient age, tumor location, and grade and extent of resection between groups. Similarly, there was no significant difference in progression-free survival and overall survival between B7-H3 high and low group. CONCLUSIONS: Our study indicates variable expression and clinical role of B7-H3 in meningiomas, suggesting its potential as an immunotherapeutic target in the future.


Assuntos
Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Neoplasias Meníngeas/patologia , Meningioma/metabolismo , Adulto , Idoso , Feminino , Humanos , Imunoterapia/métodos , Masculino , Neoplasias Meníngeas/metabolismo , Meningioma/patologia , Pessoa de Meia-Idade , Análise Serial de Tecidos/métodos
8.
Mol Immunol ; 117: 20-28, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731055

RESUMO

BACKGROUND: LncRNA NEAT1 was associated with the tumorigenesis of multiple myeloma (MM). However, the mechanisms of M2 macrophage polarization involved with NEAT1 in MM are still unknown. METHODS: Bone marrow samples, multiple myeloma cells RPMI 8226 and monocyte cell line THP-1 were used in this study. The expression of NEAT1 and miR-214 was modified by transfection with the shNEAT1 or miR-214 inhibitor. The expression of NEAT1, miR-214 and B7-H3 in MM patient tissues and cells was analyzed by RT-qPCR. ELISA assay was used to determine the release of B7-H3 in the supernatant of cell culture. The patient survival curve was analyzed using Kaplan-Meier method. The macrophage polarization markers were examined by RT-qPCR and western blotting. The interaction between NEAT1, miR-214 and B7-H3 was analyzed by Dual-Luciferase reporter and RIP assays. AG490 was used to block the JAK2/STAT3 signaling. Co-culture of THP-1 and RPMI 8226 cells was used for macrophage polarization. RESULTS: NEAT1 and B7-H3 were up-regulated, but miR-214 was obviously down-regulated in MM patients. B7-H3, NEAT1 and miR-214 were associated with overall survival time of MM patients. NEAT1 silencing induced miR-214 and inhibited the expression and release of B7-H3 and then suppressed M2 macrophage polarization via inhibiting the JAK2/STAT3 signaling. NEAT1 directly targeted miR-214, and miR-214 directly bound to B7-H3. MiR-214 inhibitor reversed the down-regulation and release of B7-H3 and M2 macrophage polarization caused by shNEAT1. The specific JAK2/STAT3 signaling inhibitor AG490 abrogated M2 macrophage polarization. CONCLUSION: NEAT1 promoted M2 macrophage polarization by sponging miR-214 and then regulating B7-H3, thus accelerating MM progression via the JAK2/STAT3 signaling pathway. Our study revealed novel mechanisms of M2 macrophage polarization and provided new potential clinical therapeutic targets for MM.


Assuntos
Antígenos B7/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , Mieloma Múltiplo/imunologia , RNA Longo não Codificante/imunologia , Antígenos B7/metabolismo , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Ativação de Macrófagos , Macrófagos/metabolismo , MicroRNAs/metabolismo , Mieloma Múltiplo/metabolismo , RNA Longo não Codificante/metabolismo
10.
Microbiol Immunol ; 64(1): 63-71, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31552680

RESUMO

Specific tumor microenvironment signaling might prevent the maturation of dendritic cells (DCs) with tolerogenic and immunosuppressive potential accounting for antigen-specific unresponsiveness in the lymphoid organs and in the periphery. In the present study, dendritic cells treated with LLC lung cancer cell or 4T1 breast cancer cell culture supernatants significantly down-regulated the expression of co-stimulatory molecules MHC-II, CD40, CD80, but up-regulated the inhibitory molecule PD-L1/L2, VISTA, and increased the messengerRNA levels of interleukin (IL)-6, arginase I, and IL-10, but decreased tumor necrosis factor-α and IL-12a. RNA was isolated from the dendritic cells with or without tumor supernatant stimulation and RNA sequencing was done. Then the differential expression genes were sorted, the candidate genes were analyzed and pathway enrichment analysis was done, and the associated protein-protein interaction network (PPI) was established. After integrated bioinformatical analysis, 405 (279 up-regulated and 126 down-regulated) consistently differential expression genes were identified. Using gene ontology and pathway analysis, it was found that differential expression genes were mainly enriched in the immune response, cell-cell interaction, hemostasis, and cell surface interactions with the vascular wall. The PPI data demonstrated that 236 nodes were classified with 1072 edges, and the most remarkable three modules involved 53 central node genes associated with cell survival, cell-substrate adhesion, chemotaxis, migration, immune response, and complement receptor mediated signaling pathway. These findings revealed the immune status of dendritic cells in the tumor environment.


Assuntos
Biologia Computacional , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Microambiente Tumoral/imunologia , Antígenos B7/metabolismo , Antígeno B7-1/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias da Mama , Antígenos CD40/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-12 , Neoplasias Pulmonares , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Mapas de Interação de Proteínas , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
11.
Cancer Immunol Immunother ; 69(1): 33-42, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31781843

RESUMO

Blockading programmed death ligand 1 (PD-L1) shows promising results in patients with some cancers, but not in those with ovarian cancer. V-domain Ig suppressor of T cell activation (VISTA) is a recently discovered immune checkpoint protein that suppresses T cell activation. This study aimed to investigate the expression and clinical significance of VISTA in ovarian cancer as well as its relationship with PD-L1. VISTA and PD-L1 levels in 146 ovarian cancer samples were assessed using immunohistochemistry. We investigated the association between VISTA and other clinicopathological variables, including survival. The associations between the VISTA-encoding C10orf54 gene, other immune checkpoints, and survival were analyzed. VISTA was detected in 51.4% of all samples and 46.6% of PD-L1-negative samples; it was expressed in 28.8%, 35.6%, and 4.1% of tumor cells (TCs), immune cells (ICs), and endothelial cells, respectively. Furthermore, VISTA expression was associated with pathologic type and PD-L1 expression. Moreover, VISTA expression in TCs, but not in ICs, was associated with prolonged progression-free and overall survival in patients with high-grade serous ovarian cancer. The expression of C10orf54 mRNA was associated with prolonged overall survival and immune escape-modulating genes. These results showed that VISTA expression in ovarian tumor cells was associated with a favorable prognosis in patients with high-grade serous ovarian cancer; however, additional studies are required to better understand the expression and role of VISTA in ovarian cancer.


Assuntos
Antígenos B7/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/mortalidade , Cistadenocarcinoma/mortalidade , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Antígenos B7/imunologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma/imunologia , Cistadenocarcinoma/patologia , Procedimentos Cirúrgicos de Citorredução , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Ovariectomia , Ovário/patologia , Ovário/cirurgia , Prognóstico , Intervalo Livre de Progressão , Evasão Tumoral/imunologia , Adulto Jovem
12.
Clin Exp Dermatol ; 45(1): 30-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31056761

RESUMO

BACKGROUND: The co-stimulatory molecule B7-H3, a cell surface transmembrane glycoprotein, was assessed for its functional and prognostic role in lichen simplex chronicus (LSC). AIM: To investigate if abnormal expression of the co-stimulatory molecule B7-H3 in LSC is associated with Langerhans cell (LC) expansion. METHODS: We used immunohistochemistry to stain LSC skin tissue, and evaluated if the immunostaining of B7-H3 and interleukin (IL)-6 was significantly different. RESULTS: Our results indicated that B7-H3 is abnormally expressed in LSC skin tissue and positively regulates LC expansion. We also found that IL-6 might modulate B7-H3 expression. Moreover, LC expansion in LSC leads to the proliferation of T cells. CONCLUSIONS: Our study indicates the potential value of immunotherapy as a treatment for LSC.


Assuntos
Antígenos B7/metabolismo , Interleucina-6/metabolismo , Células de Langerhans/metabolismo , Neurodermatite/metabolismo , Pele/metabolismo , Adolescente , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neurodermatite/imunologia , Pele/imunologia , Adulto Jovem
13.
Semin Immunol ; 42: 101308, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31604531

RESUMO

V-domain Ig suppressor of T cell activation (VISTA) is a novel checkpoint regulator with limited homology to other B7 family members. The constitutive expression of VISTA on both the myeloid and T lymphocyte lineages coupled to its important role in regulating innate and adaptive immune responses, qualifies VISTA to be a promising target for immunotherapeutic intervention. Studies have shown differential impact of agonistic and antagonistic targeting of VISTA, providing a unique landscape for influencing the outcome of cancer and inflammatory diseases.


Assuntos
Antígenos B7/imunologia , Neoplasias/imunologia , Imunidade Adaptativa , Animais , Humanos , Imunidade Inata , Imunoterapia , Neoplasias/terapia
14.
Nature ; 574(7779): 565-570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645726

RESUMO

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.


Assuntos
Antígenos B7/química , Antígenos B7/metabolismo , Glicoproteínas de Membrana/metabolismo , Linfócitos T/metabolismo , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Antígenos B7/antagonistas & inibidores , Antígenos B7/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Cristalografia por Raios X , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Feminino , Histidina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
15.
Nat Immunol ; 20(11): 1425-1434, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611702

RESUMO

Although immunotherapeutics targeting the inhibitory receptors (IRs) CTLA-4, PD-1 or PD-L1 have made substantial clinical progress in cancer, a considerable proportion of patients remain unresponsive to treatment. Targeting novel IR-ligand pathways in combination with current immunotherapies may improve clinical outcomes. New clinical immunotherapeutics target T cell-expressed IRs (LAG-3, TIM-3 and TIGIT) as well as inhibitory ligands in the B7 family (B7-H3, B7-H4 and B7-H5), although many of these targets have complex biologies and unclear mechanisms of action. With only modest clinical success in targeting these IRs, current immunotherapeutic design may not be optimal. This Review covers the biology of targeting novel IR-ligand pathways and the current clinical status of their immunotherapeutics, either as monotherapy or in combination with antibody to PD-1 or to its ligand PD-L1. Further understanding of the basic biology of these targets is imperative to the development of effective cancer immunotherapies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Antígenos B7/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Antígenos CD/imunologia , Doenças Autoimunes/imunologia , Antígenos B7/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Quimioterapia Combinada/métodos , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Ligantes , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
16.
EBioMedicine ; 47: 33-43, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31466914

RESUMO

BACKGROUND: The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM. METHODS: We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models. FINDINGS: B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines. INTERPRETATION: We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. FUND: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund.


Assuntos
Antígenos B7/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Antígenos B7/genética , Biomarcadores , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/imunologia , Glioblastoma/mortalidade , Glioblastoma/terapia , Humanos , Imunofenotipagem , Imunoterapia Adotiva , Camundongos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J BUON ; 24(3): 1120-1127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424670

RESUMO

PURPOSE: B7-H3, a member of the B7 family of immune regulatory ligands, plays a critical role in the T cell-mediated immune response. It is broadly expressed in several human cancers and leads to poor prognosis. Nevertheless, the clinical significance of B7-H3 expression in colorectal cancer (CRC) remains unclear. METHODS: The serum B7-H3, B7-H1, cancer-associated carbohydrate antigen-50 (CA-50) and carcinoembryonic antigen (CEA) expressions in patients with CRC, benign gastrointestinal diseases, and healthy controls were measured by ELISA. The miRNAs that target B7-H3 were predicted by using the miRTarBase. Real-time PCR was performed to examine their expressions in patients with CRC. RESULTS: B7-H3, B7-H1, and CA-50 expressions were higher in patients with CRC than those in healthy controls and the patients with benign gastrointestinal diseases. B7-H3 expression was correlated with TNM stage and metastasis. It was predicted that B7-H3 was a target of miR-1301-3p, miR-335-5p, and miR-28-5p and its expression was negatively related to these three miRNAs expressions. Serum miR-1301-3p, miR-335-5p, and miR-28-5p expressions were also correlated with the TNM stage and metastasis. CONCLUSION: Our results indicated that serum miR-1301-3p, miR-28-5p, miR-335-5p, and B7-H3 expressions were correlated with pathological stages of CRC and metastasis and may therefore serve as novel biomarkers for CRC diagnosis and treatment.


Assuntos
Antígenos B7/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/imunologia , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374878

RESUMO

CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins - important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented. Using well-known in vitro methods: NMR binding assay, HTRF and cell-based activation assays, we clearly show that there is no direct binding between CA-170 and PD-L1. To strengthen our reasoning, we performed control experiments on AUNP-12 - a 29-mer peptide, which is a precursor of CA-170. Positive controls consisted of the well-documented small-molecule PD-L1 inhibitors: BMS-1166 and peptide-57.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Imunoterapia , Neoplasias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Antígenos B7/antagonistas & inibidores , Antígenos B7/química , Antígeno B7-H1/química , Humanos , Espectroscopia de Ressonância Magnética , Neoplasias/imunologia , Ligação Proteica/efeitos dos fármacos
19.
Immunol Res ; 67(2-3): 202-211, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31292886

RESUMO

B7-H3 is a cell surface molecule in the immunoglobulin superfamily that has been shown to perform both immunological and non-immunological functions. It has also been found that vascular endothelial growth factor (VEGF) is an important molecule in the modulation of endothelial cell behavior. In this study, we analyzed the serum expression of B7-H3 in 113 rheumatoid arthritis and systemic lupus erythematous patients using the ELISA and found a positive correlation between B7-H3 and VEGF. Next, we investigated the involvement of B7-H3 in angiogenesis using human umbilical vein endothelial cells (HUVECs) with transient knockdown of B7-H3 and an in vivo Matrigel model. Data from the in vitro experiments showed that B7-H3 increased cell proliferation, migration, and tube formation, and correlated with the expression of VEGF. Furthermore, B7-H3 affected the formation of functional vascular networks in Matrigel plugs, which were dissected from mice injected with different HUVECs. Our data suggest that B7-H3 promotes angiogenesis through the enhancement of VEGF secretion. This is the first study proposing a significant role for B7-H3 in the promotion of angiogenesis and may provide further understanding of this gene's biological function.


Assuntos
Antígenos B7/metabolismo , Células Endoteliais/metabolismo , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Artrite Reumatoide/sangue , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Antígenos B7/sangue , Antígenos B7/genética , Biomarcadores , Movimento Celular , Proliferação de Células , Células Cultivadas , Imunofluorescência , Células Endoteliais da Veia Umbilical Humana , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Neovascularização Fisiológica/genética
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