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1.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199417

RESUMO

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC50 = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (KD = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/citologia , Antígeno B7-H1/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Interferon gama/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Cultura Primária de Células , Receptor de Morte Celular Programada 1/química , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
2.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066087

RESUMO

Immune evasion is a key strategy adopted by tumor cells to escape the immune system while promoting their survival and metastatic spreading. Indeed, several mechanisms have been developed by tumors to inhibit immune responses. PD-1 is a cell surface inhibitory receptor, which plays a major physiological role in the maintenance of peripheral tolerance. In pathological conditions, activation of the PD-1/PD-Ls signaling pathway may block immune cell activation, a mechanism exploited by tumor cells to evade the antitumor immune control. Targeting the PD-1/PD-L1 axis has represented a major breakthrough in cancer treatment. Indeed, the success of PD-1 blockade immunotherapies represents an unprecedented success in the treatment of different cancer types. To improve the therapeutic efficacy, a deeper understanding of the mechanisms regulating PD-1 expression and signaling in the tumor context is required. We provide an overview of the current knowledge of PD-1 expression on both tumor-infiltrating T and NK cells, summarizing the recent evidence on the stimuli regulating its expression. We also highlight perspectives and limitations of the role of PD-L1 expression as a predictive marker, discuss well-established and novel potential approaches to improve patient selection and clinical outcome and summarize current indications for anti-PD1/PD-L1 immunotherapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Humanos , Neoplasias/fisiopatologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Evasão Tumoral
3.
Aging (Albany NY) ; 13(12): 16656-16666, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34170847

RESUMO

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.


Assuntos
Neointima/metabolismo , Neointima/patologia , Receptor de Morte Celular Programada 1/metabolismo , Veias/metabolismo , Veias/patologia , Animais , Humanos , Hiperplasia/metabolismo , Injeções Intraperitoneais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia , Água
4.
Aging (Albany NY) ; 13(10): 13626-13643, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-34091441

RESUMO

BACKGROUND: E2F2 is a member of the E2F transcription factor family and has important but not fully understood biological functions in cancers. The biological role of E2F2 in gastric cancer (GC) also remains unclear. METHODS: We examined the expression levels of E2F2 in GC using publicly available datasets such as TIMER, Oncomine, GEPIA, UALCAN, etc., and in our patient cohort, using quantitative real-time PCR, western blotting, and immunohistochemistry. We further investigated the effects of E2F2 on phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling, autophagy, and the migration and invasion of GC cells by the wound healing assay, Transwell assay and transmission electron microscopy. RESULTS: E2F2 was highly expressed in both GC tissues and cells compared with normal gastric tissues/cells. High E2F2 expression was associated with poor overall survival (OS). In addition, the expression of E2F2 in GC was strongly correlated with a variety of immune markers. E2F2 overexpression promoted the migration and invasiveness of GC cells in vitro through inhibition of PI3K/Akt/mTOR-mediated autophagy. CONCLUSION: High E2F2 expression was associated with the characteristics of invasive tumors and poor prognosis. E2F2 also had potential modulatory effects on tumor immunity. We discovered a novel function of E2F2 in the regulation of PI3K/Akt/mTOR-mediated autophagy and the downstream processes of cell migration and invasion.


Assuntos
Autofagia , Fator de Transcrição E2F2/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Metilação de DNA/genética , Fator de Transcrição E2F2/genética , Fator de Transcrição E2F2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Masculino , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Mapas de Interação de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/genética
5.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063096

RESUMO

Programmed cell death protein 1 (PD-1), a receptor on T cells, and its ligand, PD-L1, have been a topic of much interest in cancer research. Both tumour and virus-infected cells can upregulate PD-L1 to suppress cytotoxic T-cell killing. Research on the PD-1/PD-L1 axis has led to the development of anti-PD-1/PD-L1 immune checkpoint blockades (ICBs) as promising cancer therapies. Although effective in some cancer patients, for many, this form of treatment is ineffective due to a lack of immunogenicity in the tumour microenvironment (TME). Despite the development of therapies targeting the PD-1/PD-L1 axis, the mechanisms and pathways through which these proteins are regulated are not completely understood. In this review, we discuss the latest research on molecules of inflammation and innate immunity that regulate PD-L1 expression, how its expression is regulated during viral infection, and how it is modulated by different cancer therapies. We also highlight existing research on the development of different combination therapies with anti-PD-1/PD-L1 antibodies. This information can be used to develop better cancer immunotherapies that take into consideration the pathways involved in the PD-1/PD-L1 axis, so these molecules do not reduce their efficacy, which is currently seen with some cancer therapies. This review will also assist in understanding how the TME changes during treatment, which will provide further rationale for combination therapies.


Assuntos
Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Viroses/metabolismo , Animais , Autoimunidade , Antígeno B7-H1/metabolismo , Humanos , Modelos Biológicos , Neoplasias/patologia , Neoplasias/terapia
6.
Nat Commun ; 12(1): 3530, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112755

RESUMO

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Neoplasias/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Linfoma/genética , Linfoma/metabolismo , Linfoma/mortalidade , Melanoma/genética , Melanoma/metabolismo , Melanoma/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/deficiência , Monoaminoxidase/genética , Inibidores da Monoaminoxidase/uso terapêutico , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , RNA-Seq , Espécies Reativas de Oxigênio/metabolismo , Análise de Célula Única , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Commun ; 12(1): 3414, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099731

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Lactamas Macrocíclicas/farmacologia , Neutrófilos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Neutrófilos/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
8.
Hematol Oncol ; 39 Suppl 1: 39-45, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105815

RESUMO

The treatment of classical Hodgkin lymphoma in young patients is one of the success stories of modern medicine. The use of risk- and response-adapted approaches to guide treatment decisions has led to impressive cure rates while reducing the long-term toxicity associated with more intensive therapies. Tissue biomarkers have not yet proven more effective than clinical characteristics for risk stratification of patients at presentation, but functional imaging features such as metabolic tumor volume may be used to predict response, if early observations can be validated. The success of treatment in younger patients has unfortunately not been mirrored in those over 60, where complex decision-making is often required, with a paucity of data from clinical trials. The use of PD1 blocking antibodies and brentuximab vedotin in this cohort, either alone or in combination with chemotherapy, may provide attractive options. The incorporation of frailty assessment, quality-of-life outcomes, and specialist geriatric input is also important to ensure the best outcomes for this diverse group.


Assuntos
Biomarcadores Tumorais , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias , Medicina de Precisão , Receptor de Morte Celular Programada 1 , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo
9.
Int J Nanomedicine ; 16: 3241-3254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007176

RESUMO

Purpose: Immune checkpoint inhibitors (ICIs) and sonodynamic therapy (SDT) are types of immunotherapy. In order to combine soluble programmed cell death protein 1 (sPD-1)-mediated immune checkpoint therapy and chlorin e6 (Ce6)-assisted SDT, nanobubbles (NBs) were generated to simultaneously load sPD-1 and Ce6. Materials and Methods: The sPD-1/Ce6-NBs, which were prepared by thin-film hydration and mechanical oscillation, had a stable physical condition, and delivered sPD-1 and Ce6 in a targeted manner. NBs could strengthen tumor suppression by increasing tumor-targeting accumulation of Ce6 and sPD-1, and by inducing ultrasound-targeted NB destruction. A mouse H22 cell hepatoma xenograft model was used to evaluate the synergetic immunotherapeutic effect and mechanism of sPD-1/Ce6-NBs. Results: By observing the tumor inhibition rate, tissue and cell apoptosis, apoptosis-related genes and protein expression, the best immunotherapeutic effect was exhibited by the sPD-1/Ce6-NBs group. The immunotherapeutic mechanism initially demonstrated that when tumor cells were transfected by sPD-1 delivered by NBs, which downregulated the expression of programmed death-ligand 1 (PD-L1) in tumor cells, and blocked the PD-1/PD-L1 signaling pathway, which improved T-cell-mediated tumor inhibition. Furthermore, ICIs combined with SDT induced immunogenic cell death by translocating calreticulin to the cell surface and then synergistically enhancing antitumor immune responses. Conclusion: In conclusion, sPD-1/Ce6-NBs were successfully designed. Ultrasound-mediated sPD-1/Ce6-NBs are potentially effective delivery systems for combination immunotherapy of hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Imunoterapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Nanopartículas/química , Porfirinas/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Porfirinas/farmacocinética , Porfirinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Carga Tumoral
10.
Biomed Res Int ; 2021: 8811751, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33987445

RESUMO

It is aimed at investigating the changes of serum soluble programmed death-ligand 1 (sPD-L1) expression level in nonsmall cell lung cancer (NSCLC) before and after radiotherapy, the correlation of PD-L1, PD-1, and proteins of Akt (protein kinase B), mTOR, and HIF-1α, and the molecular mechanism of the PD-1/PD-L1 pathway in the development of NSCLS. A total of 126 NSCLC patients receiving radiotherapy in Liaoning Cancer Hospital from September 2018 to September 2019 were selected as the observation group, and another 58 healthy volunteers were selected as the control group. NSCLC patients were divided into group A (stage I-II, stereotactic radiotherapy) and group B (stage III, intensity-modulated radiation therapy) according to the cancer stage. The efficacy of radiotherapy was evaluated, and sPD-L1 expression was detected by ELISA. The immunohistochemical staining was adopted to detect protein expressions of Akt, mTOR, and HIF-1α in NSCLC tissues. The correlation between their expression and expression of PD-L1 and PD-1 was analyzed. The results showed that the overall response rate (ORR) of group A was 89.29%, the clinical benefit response (CBR) was 96.43%, the median survival time (MST) was 25 months, and the survival rate within three years was 72.56%. In group B, the ORR was 70.41%, the CBR was 97.96%, the MST was 18 months, and the survival rate within three years was 34.67%. Comparison of overall serum sPD-L1 expression in the control group, group A, and group B and between groups before radiotherapy was statistically significant (P < 0.01). After radiotherapy, serum sPD-L1 expression in group A and group B decreased compared with that before radiotherapy (P < 0.01). Among NSCLC patients, the positive expression rate of Akt, mTOR, and HIF-1α was 71.32%, 41.26%, and 80.65%, respectively. PD-L1 expression and Akt, mTOR, and HIF-1α expression showed a significant correlation. PD1 expression and Akt, mTOR, and HIF-1α expression also showed a significant correlation. It indicated that the expression level of sPD-L1 in NSCLC patients was higher than that in normal subjects, but the expression level of sPD-L1 was decreased after radiotherapy. PD-1/PD-L1 may play important roles in NSCLC procession through the Akt/mTOR and HIF-1α pathway.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1/metabolismo , Idoso , Antígeno B7-H1/sangue , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Estudos de Casos e Controles , Feminino , Humanos , Pulmão/química , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/sangue
11.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946261

RESUMO

Programmed cell death-1 (PD-1), which is a molecule involved in the inhibitory signal in the immune system and is important due to blocking of the interactions between PD-1 and programmed cell death ligand-1 (PD-L1), has emerged as a promising immunotherapy for treating cancer. In this work, molecular dynamics simulations were performed on complex systems consisting of the PD-L1 dimer with (S)-BMS-200, (R)-BMS-200 and (MOD)-BMS-200 (i.e., S, R and MOD systems) to systematically evaluate the inhibitory mechanism of BMS-200-related small-molecule inhibitors in detail. Among them, (MOD)-BMS-200 was modified from the original (S)-BMS-200 by replacing the hydroxyl group with a carbonyl to remove its chirality. Binding free energy analysis indicates that BMS-200-related inhibitors can promote the dimerization of PD-L1. Meanwhile, no significant differences were observed between the S and MOD systems, though the R system exhibited a slightly higher energy. Residue energy decomposition, nonbonded interaction, and contact number analyses show that the inhibitors mainly bind with the C, F and G regions of the PD-L1 dimer, while nonpolar interactions of key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 on both PD-L1 monomers are the dominant binding-related stability factors. Furthermore, compared with (S)-BMS-200, (R)-BMS-200 is more likely to form hydrogen bonds with charged residues. Finally, free energy landscape and protein-protein interaction analyses show that the key residues of the PD-L1 dimer undergo remarkable conformational changes induced by (S)-BMS-200, which boosts its intimate interactions. This systematic investigation provides a comprehensive molecular insight into the ligand recognition process, which will benefit the design of new small-molecule inhibitors targeting PD-L1 for use in anticancer therapy.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Multimerização Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Termodinâmica
12.
J Med Chem ; 64(11): 7646-7666, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34037385

RESUMO

Two series of novel o-(biphenyl-3-ylmethoxy)nitrophenyl compounds (A1-31 and B1-17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Checkpoint Imunológico/síntese química , Nitrobenzenos/química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Feminino , Humanos , Inibidores de Checkpoint Imunológico/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Interferon gama/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Nitrobenzenos/metabolismo , Nitrobenzenos/farmacologia , Nitrobenzenos/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Med Chem ; 64(11): 7390-7403, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34056906

RESUMO

With the successful clinical application of anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies (mAb), targeting the PD-1/PD-L1 interaction has become a promising method for the discovery of cancer therapy. Due to the inherent limitations of antibodies, it is necessary to search for small-molecule inhibitors against the PD-1/PD-L1 axis. We report the design, synthesis, and evaluation in vitro and in vivo of a series of novel biphenyl pyridines as the inhibitors of PD-1/PD-L1. 2-(((2-Methoxy-6-(2-methyl-[1,1'-biphenyl]-3-yl)pyridin-3-yl)methyl)amino)ethan-1-ol (24) was found to inhibit the PD-1/PD-L1 interaction with an IC50 value of 3.8 ± 0.3 nM and enhance the killing activity of tumor cells by immune cells. Compound 24 displays great pharmacokinetics (oral bioavailability of 22%) and significant in vivo antitumor activity in a CT26 mouse model. Flow cytometry and immunohistochemistry data indicated that compound 24 activates the immune activity in tumors. These results suggest that compound 24 is a promising small-molecule inhibitor against the PD-1/PD-L1 axis and merits further development.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Piridinas/química , Bibliotecas de Moléculas Pequenas/química , Animais , Antígeno B7-H1/antagonistas & inibidores , Sítios de Ligação , Compostos de Bifenilo/química , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Meia-Vida , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Camundongos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Mapas de Interação de Proteínas/efeitos dos fármacos , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 12(1): 2746, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980853

RESUMO

Despite the clinical success of blocking its interactions, how PD-1 inhibits T-cell activation is incompletely understood, as exemplified by its potency far exceeding what might be predicted from its affinity for PD-1 ligand-1 (PD-L1). This may be partially attributed to PD-1's targeting the proximal signaling of the T-cell receptor (TCR) and co-stimulatory receptor CD28 via activating Src homology region 2 domain-containing phosphatases (SHPs). Here, we report PD-1 signaling regulates the initial TCR antigen recognition manifested in a smaller spreading area, fewer molecular bonds formed, and shorter bond lifetime of T cell interaction with peptide-major histocompatibility complex (pMHC) in the presence than absence of PD-L1 in a manner dependent on SHPs and Leukocyte C-terminal Src kinase. Our results identify a PD-1 inhibitory mechanism that disrupts the cooperative TCR-pMHC-CD8 trimolecular interaction, which prevents CD8 from augmenting antigen recognition, explaining PD-1's potent inhibitory function and its value as a target for clinical intervention.


Assuntos
Antígenos CD8/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/imunologia , Antígenos CD8/metabolismo , Cálcio/metabolismo , Humanos , Ativação Linfocitária , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo
15.
J Med Chem ; 64(9): 5519-5534, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33938739

RESUMO

Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.


Assuntos
Antineoplásicos/química , Antígeno B7-H1/metabolismo , Indóis/química , Receptor de Morte Celular Programada 1/metabolismo , Tiazóis/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Indóis/metabolismo , Indóis/farmacologia , Indóis/uso terapêutico , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Mapas de Interação de Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade
16.
Ann Clin Lab Sci ; 51(2): 174-181, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941556

RESUMO

The activation of the programmed cell death one (PD1)/PD1 ligand (PD-L1) immune checkpoint pathway is a mechanism of immune evasion characterized by the upregulation of PD-L1 expression by tumor cells and by the tumor microenvironment. This activation leads to the inhibition of PD1-positive T cells and to a decrease in the anti-tumor immune response. Plasmablastic lymphoma (PBL) is an aggressive type of large B-cell lymphoma with limited studies on the frequency of PD1 and PD-L1 expressions and their clinical impact. As PBL is associated with immune suppression in immunocompromised individuals, we hypothesize that the PD1/PD-L1 axis may be relevant in this type of lymphoma. Our study demonstrates a subset of PBL cases with a higher PD-L1 expression by tumor cells [nPD-L1high, in 4 of 21 (19%) cases] and by tumor microenvironment [macrophages/stromal cells, sPD-L1high, in 9 of 21 (43%) cases]. While nPD-L1 expression showed no significant correlation with PD1 expression on tumor-infiltrating lymphocytes, or other clinicopathological parameters, it positively correlated with sPD-L1 expression. Moreover, patients with nPD-L1high had a tendency towards a shorter overall survival (median 9.3 vs. 25.5 months in nPD-L1low patients). In conclusion, our study provides a rationale to identify, by immunohistochemistry, a subset of nPD-L1high patients who may benefit from clinical trials of PD1/PD-L1 checkpoint blockade. Further studies on large cohorts are needed to investigate prognostic and predictive biomarkers for the PD1/PD-L1 pathway in PBL patients.


Assuntos
Antígeno B7-H1/metabolismo , Linfoma Plasmablástico/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Antígeno B7-H1/genética , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Linfoma Plasmablástico/genética , Linfoma Plasmablástico/fisiopatologia , Prognóstico , Receptor de Morte Celular Programada 1/genética , Células Estromais/metabolismo , Texas , Microambiente Tumoral/genética
17.
Medicine (Baltimore) ; 100(17): e25555, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907102

RESUMO

BACKGROUND: The immune checkpoint programmed cell death-1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. However, the relationship between the expression of soluble programmed cell death-1(sPD-1) and cancer pain is controversial. The purpose of this study was to evaluate the relationship between sPD-1 expression level and cancer pain through meta-analysis. METHODS: Studies were selected from Pubmed, Web of science, Embase, Google Scholar, and Chinese National Knowledge Infrastructure, and the Chinese Biomedical Literature Database based on inclusion and exclusion criteria. The standard mean difference (SMD) and 95% confidence interval (CI) were calculated using the random-effect model or fixed-effect model to assess the association between sPD-1 expression level and cancer pain. All analyses were performed with the Stata 14 software. RESULTS: This review will be disseminated in print by peer-review. CONCLUSION: The results of this study will help us to determine whether the expression level of sPD-1 is related to cancer pain. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not endanger participant rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/WDPUY.


Assuntos
Dor do Câncer/etiologia , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Humanos , Metanálise como Assunto , Neoplasias/complicações , Projetos de Pesquisa , Revisões Sistemáticas como Assunto
18.
Cell Immunol ; 364: 104347, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33838447

RESUMO

Myeloid-derived suppressor cells (MDSC) are important immune-regulatory cells but their identification remains difficult. Here, we provide a critical view on selected surface markers, transcriptional and translational pathways commonly used to identify MDSC by specific, their developmental origin and new possibilities by transcriptional or proteomic profiling. Discrimination of MDSC from their non-suppressive counterparts is a prerequisite for the development of successful therapies. Understanding the switch mechanisms that direct granulocytic and monocytic development into a pro-inflammatory or anti-inflammatory direction will be crucial for therapeutic strategies. Manipulation of these myeloid checkpoints are exploited by tumors and pathogens, such as M. tuberculosis (Mtb), HIV or SARS-CoV-2, that induce MDSC for immune evasion. Thus, specific markers for MDSC identification may reveal also novel molecular candidates for therapeutic intervention at the level of MDSC.


Assuntos
Biomarcadores/metabolismo , Perfilação da Expressão Gênica/métodos , Células Supressoras Mieloides/imunologia , Proteômica/métodos , Transdução de Sinais/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Células Cultivadas , Humanos , Camundongos , Células Supressoras Mieloides/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Transdução de Sinais/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
19.
BMC Cancer ; 21(1): 399, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849473

RESUMO

BACKGROUND: The purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining. METHODS: Consecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs). RESULTS: In total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43-85] and PA: n = 106, 65 years [range, 45-82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2-42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3-27.6) in the PE group versus 18.3 months (95% CI, 16.5-20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39-0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7-7.8] for PE vs. 4.9 months for PA (95% CI, 3.2-6.4) for PA; HR 0.55, 95% CI, 0.41-0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable. CONCLUSIONS: Among selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
20.
Nat Commun ; 12(1): 2425, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893275

RESUMO

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream ß-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells' P-glycoproteins (P-gp) through the JMJD1A/ß-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/farmacologia , Hidroxiquinolinas/farmacologia , Imunoterapia/métodos , Neoplasias/terapia , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Doxorrubicina/administração & dosagem , Células HCT116 , Humanos , Hidroxiquinolinas/administração & dosagem , Hidroxiquinolinas/química , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
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