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1.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360781

RESUMO

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA-CD45RO+CCR7-) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Inibidores de Checkpoint Imunológico/administração & dosagem , Melanoma , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Citometria de Fluxo , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Memória Imunológica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/imunologia
2.
Nat Med ; 27(8): 1432-1441, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239137

RESUMO

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1ß in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.


Assuntos
Antígeno CTLA-4/imunologia , Microbioma Gastrointestinal , Receptor de Morte Celular Programada 1/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Interleucina-1beta/imunologia , Melanoma , Camundongos , Camundongos Endogâmicos C57BL
3.
Clin Immunol ; 229: 108800, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34289424

RESUMO

The study aimed to investigate the soluble programmed death-1 (sPD-1) and its ligand (sPD-L1) levels in systemic juvenile idiopathic arthritis (sJIA) patients and elucidate its underlying immunomodulatory mechanisms. Plasma levels of sPD-1, sPD-L1 and related cytokines and proteins were detected using an enzyme-linked immunosorbent assay (ELISA) and Luminex. The effects of PD-1/PD-L1 signal on mDC (myeloid dendritic cell) and IL-6 secretion were measured using flow cytometry. The results revealed decreased levels of sPD-1 in sJIA patients negatively correlated with JADAS-27, PGA, PtGA and CRP. sJIA patients had lower CD86 and MHC-II expression on mDC. When blocking PD-1/PD-L1 signal, IL-6 secretion of DC were increased. Our finding displayed downregulated sPD-1 was related with clinical indicators and could be a new biomarker for sJIA diagnosis. The reduced membrane and soluble forms of PD-1/PD-L1 might take part in sJIA pathogenesis by enhancing mDC proliferation and IL-6 secretion.


Assuntos
Artrite Juvenil/imunologia , Antígeno B7-H1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Artrite Juvenil/sangue , Artrite Juvenil/diagnóstico , Antígeno B7-H1/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/sangue , Células Dendríticas/imunologia , Regulação para Baixo , Feminino , Humanos , Interleucina-6/sangue , Masculino , Receptor de Morte Celular Programada 1/sangue , Transdução de Sinais/imunologia , Solubilidade
4.
Life Sci ; 282: 119813, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256042

RESUMO

Immune checkpoint blockade has displayed substantial anti-tumor resistance in a variety of forms of cancer, but the fundamental regulation role remains unclear, and several questions continue to be addressed. PD-1/PD-L1 has been recognized as an anti-cancer drug target for several years, and through targeting the PD-1/PD-L1 signaling pathway, many monoclonal antibodies have thus far produced promising results in cancer therapy. The discovery of small-molecule inhibitors focused on the PD-1/PD-L1 signaling pathway is steadily reviving over decades, owing to the intrinsic shortcomings of the antibodies. PD-1 function and its PD-L1 or PD-L2 ligands are essential for the activation, proliferation, and cytotoxic secretion of T-cells in cancer to degenerate anti-tumor immune response. The axis PD-1/PD-L1 is important for the immune escape of cancer which has an immense impact on cancer treatment. In this review, we summarize the function of PD-1 and PD-L1 in cancer and aiming to enhance cancer therapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Antígeno B7-H1/imunologia , Humanos , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
5.
J Intern Med ; 290(3): 677-692, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34080738

RESUMO

BACKGROUND: Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10). RESULTS: COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. CONCLUSION: Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.


Assuntos
COVID-19/genética , COVID-19/imunologia , Leucócitos Mononucleares/imunologia , Transcriptoma , Imunidade Adaptativa , Adulto , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Antígenos HLA-DR/imunologia , Humanos , Imunidade Inata , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-7/imunologia , Complexo Antígeno L1 Leucocitário/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , SARS-CoV-2 , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Tromboplastina/imunologia , Tromboplastina/metabolismo
6.
Cancer Treat Rev ; 99: 102242, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34153830

RESUMO

BACKGROUND: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients. METHODS: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events. RESULTS: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy. CONCLUSIONS: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma de Células Renais/imunologia , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Renais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
PLoS One ; 16(6): e0251731, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34181666

RESUMO

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.


Assuntos
Hidroxicloroquina/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Receptor de Morte Celular Programada 1/imunologia , Animais , Azitromicina/farmacologia , Linhagem Celular Tumoral , Antagonismo de Drogas , Inibidores de Checkpoint Imunológico/imunologia , Melanoma/patologia , Camundongos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
8.
Toxicol Appl Pharmacol ; 426: 115633, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166680

RESUMO

Chronic exposure to environmental arsenic promotes lung cancer. Emerging evidence indicates that compromised host immunity, particularly T cell anti-tumor immunity, may play a critical role in cancer development. However, there is a knowledge gap in terms of the effects of arsenic exposure on T cell anti-tumor immunity and how that may contribute to arsenic lung carcinogenicity. Immunosuppression has been known as a risk factor for many types of cancer, including lung cancer. The development of cancer indicates the success of immunosuppression and escape of cancer cells from host anti-tumor immunity in which T cells are the major component. The anti-tumor immunity is mainly executed by CD8 cytotoxic T cells through their anti-tumor effector function, which can be regulated by immune checkpoint pathways. Some inhibitory receptors on the T cell membrane and their ligands form these pathways, among which programmed death-1 (PD-1), a T cell inhibitory receptor, and its ligand, programmed death-ligand 1 (PD-L1), are best characterized. A/J mice are naturally sensitive to pulmonary carcinogens, prone to develop spontaneous lung tumors later in life and have been frequently used as an animal model for lung tumorigenesis research. Chronic arsenic administration through drinking water has been shown to enhance tumor formation in the lungs of A/J mice. In the current study, using this mouse model we want to determine whether PD-1/PD-L1 plays a role in arsenic-enhanced lung tumorigenesis. The results showed that prolonged arsenic exposure up-regulated PD-1/PD-L1, increased regulatory T cells (Tregs), decreased CD8/Treg ratio, inhibited T cell antitumor function in the lungs and enhanced lung tumor formation, while inhibition of PD-1/PD-L1 restored CD8/Treg ratio and T cell anti-tumor effector function, and mitigated arsenic-enhanced lung tumorigenesis. In addition, inhibition of PD-1/PD-L1 could be a potential preventive strategy to mitigate the tumorigenic action of chronic arsenic exposure.


Assuntos
Arsênio/toxicidade , Antígeno B7-H1/imunologia , Carcinogênese/imunologia , Neoplasias Pulmonares/induzido quimicamente , Receptor de Morte Celular Programada 1/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/efeitos dos fármacos , Feminino , Imunoglobulina G/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino , Camundongos , Linfócitos T Reguladores/imunologia
9.
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
10.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073458

RESUMO

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell-cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.


Assuntos
Doenças Autoimunes/imunologia , Proliferação de Células , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Antígeno CTLA-4/imunologia , Feminino , Granzimas/imunologia , Humanos , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/citologia , Células Th17/citologia
11.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070750

RESUMO

The immune system is a fine modulator of the tumor biology supporting or inhibiting its progression, growth, invasion and conveys the pharmacological treatment effect. Tumors, on their side, have developed escaping mechanisms from the immune system action ranging from the direct secretion of biochemical signals to an indirect reaction, in which the cellular actors of the tumor microenvironment (TME) collaborate to mechanically condition the extracellular matrix (ECM) making it inhospitable to immune cells. TME is composed of several cell lines besides cancer cells, including tumor-associated macrophages, cancer-associated fibroblasts, CD4+ and CD8+ lymphocytes, and innate immunity cells. These populations interface with each other to prepare a conservative response, capable of evading the defense mechanisms implemented by the host's immune system. The presence or absence, in particular, of cytotoxic CD8+ cells in the vicinity of the main tumor mass, is able to predict, respectively, the success or failure of drug therapy. Among various mechanisms of immunescaping, in this study, we characterized the modulation of the phenotypic profile of CD4+ and CD8+ cells in resting and activated states, in response to the mechanical pressure exerted by a three-dimensional in vitro system, able to recapitulate the rheological and stiffness properties of the tumor ECM.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Matriz Extracelular/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Cultura de Células , Módulo de Elasticidade , Matriz Extracelular/química , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Hidrogéis/química , Interferon gama/genética , Interferon gama/imunologia , Ativação Linfocitária , Mecanotransdução Celular , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Reologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia
12.
Nat Immunol ; 22(7): 809-819, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140679

RESUMO

CD8+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Linfócitos T CD8-Positivos/imunologia , Doenças Transmissíveis/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Doença Crônica , Doenças Transmissíveis/genética , Doenças Transmissíveis/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Epigênese Genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais
13.
Biochem Biophys Res Commun ; 559: 176-182, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33945995

RESUMO

Oncolytic virus can selectively recognize cancer cells, target tumors, and stimulate an oncolytic and immune response. Recombinant armed oncolytic vaccinia virus has emerged as an attractive tool in oncolytic virotherapy because it has tumor-specific cytotoxicity and serves as a vector to express immune genes. A novel thymidine kinase (TK) gene-deleted oncolytic vaccinia virus (named ΔTK-Armed-VACV) armed with anti-human-programed cell death-1 protein (PD-1) antibody and anti-human-tumor necrosis factor receptor superfamily, member 9 (4-1BB) antibody genes was constructed based on Western Reserve in our previous study. The present study evaluated the ability of this virus for cancer-targeted therapy both in vitro and in vivo. A complete morphological structure of ΔTK-Armed-VACV was verified using transmission electron microscopy. The antibody was co-expressed with the replication of ΔTK-Armed-VACV in vitro assessed by Western blot analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-rboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay showed that the ΔTK-Armed-VACV exhibited significant tumor-specific cytotoxicity in vitro. The ΔTK-Armed-VACV inhibited the tumor growth in a 4T1 or A549 tumor-bearing mouse model. ELISpot assay showed that ΔTK-Armed-VACV-treated mice induced the expression of interferon-gamma, and lactate dehydrogenase-dependent cytotoxicity assay revealed that the ΔTK-Armed-VACV treatment activated tumor-specific cytotoxic T lymphocytes. The results indicated that oncolytic VACV with Western Reserve-mediated anti-human-PD-1 and anti-human-4-1BB antibody co-expression exerted a significant antitumor effect, indicating that the combination of oncolytic virotherapy and immunotherapy by the oncolytic VACV expressing one or more immune checkpoint genes might have satisfactory clinical expectations.


Assuntos
Anticorpos/genética , Neoplasias/terapia , Vírus Oncolíticos/genética , Receptor de Morte Celular Programada 1/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Vírus Vaccinia/genética , Células A549 , Animais , Anticorpos/imunologia , Feminino , Expressão Gênica , Humanos , Imunoterapia/métodos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/genética , Neoplasias/imunologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Vírus Vaccinia/imunologia
14.
Biochem Biophys Res Commun ; 560: 1-6, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-33965784

RESUMO

Cancer immunotherapy, especially treatment with monoclonal antibodies (mAbs) that block programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling, has attracted attention as a new therapeutic option for cancer. However, only a limited number of patients have responded to this treatment approach. In this study, we searched for compounds that enhance the efficacy of anti-PD-1 mAb using mixed lymphocyte reaction (MLR), which is a mixed culture system of the two key cells (dendritic and T cells) involved in tumor immunity. We found that amlexanox enhanced production of interferon (IFN)-γ, an indicator of T cell activation, by anti-PD-1 mAb. Amlexanox also induced PD-L1 expression in dendritic cells in MLR, whereas it did not stimulate interleukin-2 production by Jurkat T cells. These results suggest that amlexanox acts on dendritic cells, not T cells, in MLR. Furthermore, it enhanced the antitumor effect of the anti-PD-1 mAb in vivo in a mouse tumor-bearing model. The combination of amlexanox and anti-PD-1 mAb increased the expression of Ifng encoding IFN-γ, IFN-γ-related genes, Cd274 encoding PD-L1, and cytotoxic T cell-related genes in tumors. In conclusion, amlexanox stimulates the antitumor effect of anti-PD-1 mAb by acting on dendritic cells, which in turn activates cytotoxic T cells in tumors.


Assuntos
Aminopiridinas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Aminopiridinas/farmacologia , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Feminino , Humanos , Interferon gama/biossíntese , Células Jurkat , Teste de Cultura Mista de Linfócitos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/metabolismo
15.
Methods Mol Biol ; 2318: 281-295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34019297

RESUMO

Myc is deregulated in most-if not all-cancers, and it not only promotes tumor progression by inducing cell proliferation but is also responsible for tumor immune evasion. In a nutshell, MYC promotes the development of tumor-associated macrophages, impairs the cellular response to interferons, induces the expression of immunosuppressive molecules, and excludes tumor infiltrating lymphocytes (TILs) from the tumor site. Based on the insights into the role of MYC in promoting and regulating immune evasion by cancer cells, it is of special interest to study the different immune cell populations infiltrating the tumors. MYC inhibition has emerged as a potential new strategy for the treatment of cancer, directly inhibiting tumor progression while also counteracting the immunosuppressive tumor microenvironment, allowing an optimal anti-tumor immune response. Hence, this chapter describes a flow cytometry-based method to study the different immune cell subsets infiltrating the tumor by combining surface, cytoplasmic, and nuclear multicolor protein stainings.


Assuntos
Citometria de Fluxo/métodos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Microambiente Tumoral/imunologia , Proliferação de Células , DNA/genética , Genes myc/genética , Genes myc/fisiologia , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Microambiente Tumoral/fisiologia
16.
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
17.
Angew Chem Int Ed Engl ; 60(28): 15459-15465, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33904236

RESUMO

A tumor-targeting enhanced chemotherapy, enabled by aptamer-drug conjugate nanomicelles, is reported that boosts antitumor immune responses. Multivalent aptamer drug conjugate (ApMDC), an amphiphilic telodendrimer consisting of a hydrophilic aptamer and a hydrophobic monodendron anchored with four anticancer drugs by acid-labile linkers, was designed and synthesized. By co-self-assembly with an ApMDC analogue, in which aptamer is replaced with polyethylene glycol, the surface aptamer density of these nanomicelles can be screened to reach an optimal complementation between blood circulation and tumor-targeting ability. Optimized nanomicelles can enhance immunogenic cell death of tumor cells, which strikingly augments the tumor-specific immune responses of the checkpoint blockade in immunocompetent tumor-bearing mice. ApMDC nanomicelles represent a robust platform for structure-function optimization of drug conjugates and nanomedicines.


Assuntos
Antineoplásicos/uso terapêutico , Aptâmeros de Nucleotídeos/uso terapêutico , Imunoterapia , Nanopartículas/química , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Aptâmeros de Nucleotídeos/síntese química , Aptâmeros de Nucleotídeos/química , Micelas , Nanomedicina , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia
18.
Clin Immunol ; 229: 108742, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33905818

RESUMO

Sepsis is characterized by high mortality and poor prognosis and is one of the leading causes of death among patients in the intensive care unit (ICU). In the past, drugs that block early inflammatory responses have done little to reverse the progression of sepsis. Programmed cell death receptor 1 (PD-1) and its two ligands, programmed cell death receptor ligand 1(PD-L1) and programmed cell death receptor ligand 2 (PD-L2), are negative regulatory factors of the immune response of the body. Recently, the role of the PD-1 signaling pathway in sepsis has been widely studied. Studies showed that the PD-1 signaling pathways are closely related to the mortality and prognosis of sepsis patients. In the immunotherapy of sepsis, whether in animal experiments or clinical trials, anti-PD-1/PD-L1 antibodies have shown good promise. In this review, firstly, we focus on the immunosuppressive mechanism of sepsis and the structure and function of the PD-1 signaling pathway. The variety of the PD-1 signaling pathways in sepsis is introduced. Then, the relationship between the PD-1 signaling pathway and immune cells and organ dysfunction and the regulatory factors of the PD-1 signaling pathway in sepsis is discussed. Finally, the application of the PD-1 signaling pathway in sepsis is specifically emphasized.


Assuntos
Receptor de Morte Celular Programada 1/imunologia , Sepse/imunologia , Imunidade Adaptativa , Animais , Linfócitos B/imunologia , Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Humanos , Tolerância Imunológica , Imunidade Inata , Imunoterapia , Macrófagos/imunologia , Modelos Imunológicos , Monócitos/imunologia , Neutrófilos/imunologia , Prognóstico , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Sepse/terapia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
19.
Theranostics ; 11(12): 5955-5969, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897892

RESUMO

Anti-programmed cell death protein 1 (PD-1) therapy has shown promising efficacy in hepatocellular carcinoma (HCC), but its response rates in advanced HCC are lower than 20%. A critical reason for this is the imbalance between CD8+ T cells and tumor burden. Here, a novel concept of vascular disruption and normalization dependent on a polymeric vascular disrupting agent (VDA) poly (L-glutamic acid)-graft-methoxy poly (ethylene glycol)/combretastatin A4 (CA4-NPs) + a vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) inhibitor DC101 is applied to improve anti-PD-1 therapy, wherein CA4-NPs reduce tumor burden and DC101 simultaneously increases the number of intratumoral CD8+ T cells, successfully regulating the abovementioned imbalance in an H22 tumor model. Methods: Blood vessel density, tumor cell proliferation, and necrosis were evaluated to reveal the effects on reducing tumor burden by CA4-NP treatment. Pericyte coverage of blood vessels, tumor blood vessel perfusion, tumor hypoxia, and intratumoral immune cells were examined to verify their role in vascular normalization and immune cell homing of DC101. Furthermore, the effects of CA4-NPs + DC101 on reducing tumor burden and increasing the number of immune cells were studied. Finally, tumor suppression, intratumoral CD8+ T cell activation, and the synergistic effects of anti-PD-1 combined with CA4-NPs + DC101 were verified. Results: The tumor inhibition rate of anti-PD-1 antibody combined with CA4-NPs + DC101 reached 86.4%, which was significantly higher than that of anti-PD-1 (16.8%) alone. Importantly, the Q value reflecting the synergy between CA4-NPs + DC101 and anti-PD-1 was 1.24, demonstrating a strong synergistic effect. Furthermore, CA4-NPs + DC101 improved anti-PD-1 therapy by increasing the number of intratumoral CD8+ T cells (anti-PD-1, 0.31% vs triple drug combination, 1.18%). Conclusion: These results reveal a novel approach to enhance anti-PD-1 therapy with VDAs + VEGF/VEGFR2 inhibitors in HCC.


Assuntos
Anticorpos Monoclonais/farmacologia , Bibenzilas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Receptor de Morte Celular Programada 1/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Hipóxia Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
J Immunol ; 206(9): 2045-2051, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33846228

RESUMO

Autoreactive CD4 T cells are thought to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Recently, a subset of CD4 T cells that express high levels of programmed death-1 (PD-1) but are distinct from follicular helper T cells have been identified in the joints of RA patients and named peripheral helper T (Tph) cells. Because PD-1 is expressed on T cells chronically stimulated with the Ags, we tested a hypothesis that Tph cells are the pathogenic autoreactive CD4 T cells in RA. We found that human Tph cells in RA joints produce proinflammatory effector cytokines, including IFN-γ, TNF-α, and GM-CSF, in addition to B cell-helping cytokines, such as IL-21 and CXCL13. Flow cytometric analysis showed different bias of TCR Vß usage between PD-1high Tph cells and PD-1low/neg CD4 T cells, including Th1 cells, in the joint or memory CD4 T cells in the peripheral blood, whereas there was little difference between the latter two subsets. In line with this, deep sequencing of TCR demonstrated an overlap of expanded clones between peripheral blood memory CD4 T cells and PD-1low/neg CD4 T cells but not Tph cells in the joint. Interestingly, Tph cells preferentially exhibited autologous MLR in vitro, which required recognition of self-MHC class II and was pronounced by blocking PD-1 signaling. Taken together, these results suggest that Tph cells are the pathogenic autoreactive CD4 T cells in RA, which expand locally in the joints and are regulated by PD-1 signaling.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Quimiocina CXCL13/imunologia , Quimiocina CXCL13/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo
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