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1.
Nat Commun ; 11(1): 4858, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978382

RESUMO

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.


Assuntos
Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Metilação de DNA , Tratamento Farmacológico , Instabilidade Genômica , Humanos , Mutação , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transcriptoma , Neoplasias da Bexiga Urinária/patologia
2.
PLoS One ; 15(8): e0237646, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845913

RESUMO

Tumor antigen-primed CD8 T cells differentiate into effector T cells that kill tumor cells rapidly, whereas durable responses of CD8 T cells are required to cope with long-lasting tumor growth. However, it is not well known how persisting CD8 T cells are generated. In this study, we analyzed CD8 T cells primed by antigens in tumor-draining lymph nodes and found that CD8 T cells first differentiated into a CD62L-intermediate (CD62Lint) stage upon antigen stimulation. These cells gave rise to tumor-infiltrating CD62L-CD44high Bcl6- effector T cells and CD62L+CD44highBcl6+ memory-like T cells. Memory-like T cells within the tumor expressed CD127, CXCR3 and had the potential to proliferate significantly when they were transferred into tumor-bearing mice. Bcl6 expression in these T cells was critical because Bcl6-/-CD62L+CD44highCD8T cells within the tumor were defective in expansion after secondary transfer. Taken together, our findings show that CD62L+CD44highBcl6+ cells are generated from highly proliferating CD62Lint T cells and retain high proliferative potential, which contributes to replenishment of effector T cells within the tumor.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Lewis/patologia , Memória Imunológica/imunologia , Selectina L/metabolismo , Melanoma Experimental/patologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Animais , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Diferenciação Celular , Feminino , Selectina L/genética , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Células Tumorais Cultivadas
3.
Nat Commun ; 11(1): 3998, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778730

RESUMO

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.


Assuntos
Asma/imunologia , Asma/metabolismo , Imunidade Inata/imunologia , Linfócitos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Células Th2/metabolismo , Transcriptoma
4.
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32612152

Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Terapia de Alvo Molecular/métodos , Pneumonia Viral/imunologia , Pneumonia/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Antivirais/uso terapêutico , Apirase/antagonistas & inibidores , Apirase/genética , Apirase/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
5.
PLoS One ; 15(7): e0235518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614928

RESUMO

Interruption of the programmed death 1 (PD-1) / programmed death ligand 1 (PD-L1) pathway is an established and effective therapeutic strategy in human oncology and holds promise for veterinary oncology. We report the generation and characterization of monoclonal antibodies specific for canine PD-1 and PD-L1. Antibodies were initially assessed for their capacity to block the binding of recombinant canine PD-1 to recombinant canine PD-L1 and then ranked based on efficiency of binding as judged by flow cytometry. Selected antibodies were capable of detecting PD-1 and PD-L1 on canine tissues by flow cytometry and Western blot. Anti-PD-L1 worked for immunocytochemistry and anti-PD-1 worked for immunohistochemistry on formalin-fixed paraffin embedded canine tissues, suggesting the usage of this antibody with archived tissues. Additionally, anti-PD-L1 (JC071) revealed significantly increased PD-L1 expression on canine monocytes after stimulation with peptidoglycan or lipopolysaccharide. Together, these antibodies display specificity for the natural canine ligand using a variety of potential diagnostic applications. Importantly, multiple PD-L1-specific antibodies amplified IFN-γ production in a canine peripheral blood mononuclear cells (PBMC) concanavlin A (Con A) stimulation assay, demonstrating functional activity.


Assuntos
Anticorpos Monoclonais/imunologia , Antígeno B7-H1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Cães , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Peptidoglicano/farmacologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo
6.
Sheng Wu Gong Cheng Xue Bao ; 36(5): 969-978, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32567280

RESUMO

Drugs targeting immune checkpoint are used for cancer treatment, but resistance to single drug may occur. Combination therapy blocking multiple checkpoints simultaneously can improve clinical outcome. Therefore, we designed a recombinant protein rPC to block multiple targets, which consists of extracellular domains of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The coding sequence was inserted into expression vector and stably transfected into HEK293 cells. The culture supernatant was collected and rPC was affinity-purified. Real-time quantitative PCR was used to evaluate the expression levels of ligands for PD-1 and CTLA-4 in several human cancer cell lines. The binding of rPC with cancer cells was examined by immunofluorescence cell staining, the influence of rPC on cancer cell growth was assayed by CCK-8. The results showed that rPC could be expressed and secreted by stably transfected HEK293 cells, the purified rPC could bind to lung cancer NCI-H226 cells which have high levels of ligands for PD-1 and CTLA-4, no direct impact on cancer cell growth could be observed by rPC treatment. The recombinant protein rPC can be functionally assayed further for developing novel immunotherapeutic drugs for cancer.


Assuntos
Neoplasias Pulmonares , Proteínas Recombinantes de Fusão , Animais , Antígeno CTLA-4/genética , Proliferação de Células , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/genética , Ligação Proteica , Domínios Proteicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(22): 12288-12294, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430334

RESUMO

PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti-PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti-PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti-PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti-PD-L1 monotherapy in bladder cancer.


Assuntos
Pele/imunologia , Neoplasias da Bexiga Urinária/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Autoimunidade , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Estudos de Coortes , Humanos , Herança Multifatorial , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Pele/efeitos dos fármacos , Células Th17/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
8.
Tumori ; 106(4): 306-311, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32366210

RESUMO

BACKGROUND: The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. METHODS: We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. RESULTS: No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high (I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity (I2 = 55%). CONCLUSION: PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.


Assuntos
Antígeno B7-H1/genética , Timoma/genética , Neoplasias do Timo/genética , Adulto , Idoso , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Timoma/imunologia , Timoma/patologia , Timoma/terapia , Neoplasias do Timo/imunologia , Neoplasias do Timo/terapia
9.
Cancer Immunol Immunother ; 69(10): 1989-1999, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32393998

RESUMO

Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno CTLA-4/sangue , Neoplasias Colorretais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/sangue , Receptores Imunológicos/sangue , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Antígeno CTLA-4/genética , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/genética , Receptores Imunológicos/genética , Linfócitos T/metabolismo , Linfócitos T/patologia , Adulto Jovem
10.
Oncology ; 98(7): 501-511, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32380498

RESUMO

INTRODUCTION: Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment. METHODS: PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis. RESULTS: PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC patients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10-4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12-6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively. CONCLUSIONS: PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery.


Assuntos
Antígeno B7-H1/genética , Antígenos CD8/genética , Expressão Gênica/imunologia , Receptor de Morte Celular Programada 1/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/imunologia , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
11.
Nat Med ; 26(5): 732-740, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341578

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.


Assuntos
Sistemas CRISPR-Cas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Edição de Genes/métodos , Imunoterapia Adotiva , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/genética , Linfócitos T/transplante , Adolescente , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Estudos de Viabilidade , Feminino , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo , Resultado do Tratamento , Adulto Jovem
12.
Clin Sci (Lond) ; 134(7): 711-726, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32202617

RESUMO

Tumor-infiltrating PD-1hi dysfunctional CD8+ T cells have been identified in several tumors but largely unexplored in breast cancer (BC). Here we aimed to extensively explore PD-1hiCD8+ T cells in BC, focusing on the triple-negative BC (TNBC) subtype. Flow cytometry was used to study the phenotypes and functions of CD8+ T-cell subsets in peripheral blood and surgical specimens from treatment-naive BC patients. RNA-seq expression data generated to dissect the molecular features of tumoral PD-1neg, PD-1lo and PD-1hi CD8+ T cells. Further, the associations between tumoral PD-1hi CD8+ T cells and the clinicopathological features of 503 BC patients were explored. Finally, multiplexed immunohistochemistry (mIHC) was performed to evaluate in situ PD-1hiCD8+ T cells on the tissue microarrays (TMAs, n=328) for prognostic assessment and stratification of TNBC patients. PD-1hiCD8+ T cells found readily detectable in tumor tissues but rarely in peripheral blood. These cells shared the phenotypic and molecular features with exhausted and tissue-resident memory T cells (TRM) with a skewed TCR repertoire involvement. Interestingly, PD-1hiCD8+ T cells are in the state of exhaustion characterized by higher T-BET and reduced EOMES expression. PD-1hiCD8+ T cells found preferentially enriched within solid tumors, but predominant stromal infiltration of PD-1hiCD8+ T subset was associated with improved survival in TNBC patients. Taken together, tumoral PD-1hiCD8+ T-cell subpopulation in BC is partially exhausted, and their abundance signifies 'hot' immune status with favorable outcomes. Reinvigorating this population may provide further therapeutic opportunities in TNBC patients.


Assuntos
Biomarcadores Tumorais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Codificadores dos Receptores de Linfócitos T , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Fenótipo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Transcriptoma , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/cirurgia , Microambiente Tumoral
13.
J Pathol ; 251(2): 147-159, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32222046

RESUMO

Direct quantification of exhausted T cells in human cancer is lacking, and its predictive value for checkpoint-based treatment remains poorly investigated. We sought to systematically characterize the pan-cancer landscape and molecular hallmarks of T-cell dysfunction for the purpose of precision immunotherapy. Here, we defined a transcriptional signature for T-cell exhaustion through analyzing differential gene expression between PD-1-high and PD-1-negative CD8+ T lymphocytes from primary non-small cell lung cancer (NSCLC), followed by positive correlation tests with PDCD1 in TCGA lung carcinomas. A 78-gene signature for exhausted CD8+ T cells (GET) was identified and validated to reflect dysfunctional immune state spanning different species and disease models. We discovered that GET estimation significantly correlated with intratumoral immune cytolytic activity (CYT) and T-cell-inflamed gene expression profile (GEP) across 30 solid tumor types. Miscellaneous tumor-intrinsic and -extrinsic properties, in particular leukocyte proportions, genomic abnormalities, specific mutational signatures, and signaling pathways, were notably associated with GET levels. Furthermore, higher GET expression predicted an increased likelihood of clinical response to immune checkpoint inhibitors. These findings highlight the interrelation between T-cell exhaustion and immune cytolytic activity at the pan-cancer scale. The resulting inflamed tumor microenvironment may further crosstalk with other molecular and clinicopathological factors, which should be properly considered during immunotherapy biomarker development. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Citotoxicidade Imunológica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transcriptoma
14.
Clin Immunol ; 214: 108382, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32169439

RESUMO

With the successful treatment of B-cell lymphomas using rituximab, a monoclonal antibody targeting CD20, novel immunotherapies have developed rapidly in recent years. Immune checkpoint blockade and chimeric antigen receptor-T (CAR-T) cell therapy, which are antibody-based therapy and cell-based therapy, respectively, show promising efficacy and have been approved by the Food and Drug Administration for treating hematological malignancies. However, considering severe side effects and short-term clinical remission, the combination of CAR-T cell therapy and programmed cell-death protein-1 (PD-1) blockade has been applied to enhance therapeutic efficacy in preclinical models and clinical trials. Herein, we review the mechanism of the two therapies, show their toxicities and clinical use respectively, address their combined application, and discuss the scope of further investigations of this mechanism-based combination therapy.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Linfoma de Células B/terapia , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfoma de Células B/tratamento farmacológico , Terapia de Alvo Molecular/efeitos adversos , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Regulação para Cima
15.
Mol Cell ; 77(5): 930-931, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142689

RESUMO

Okazaki and colleagues report that PD-1 signaling mainly restrains effector function at the early stage of T cell activation. The authors find that cytokine genes require strong antigen stimulation and are more susceptible to PD-1 inhibition.


Assuntos
Receptor de Morte Celular Programada 1/genética , Linfócitos T/imunologia , Ativação Linfocitária , Transdução de Sinais , Transcriptoma
16.
Adv Exp Med Biol ; 1248: 227-250, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185713

RESUMO

In this chapter, we will sketch a story that begins with the breakdown of chromosome homeostasis and genomic stability. Genomic alterations may render tumor cells eternal life at the expense of immunogenicity. Although antitumor immunity can be primed through neoantigens or inflammatory signals, tumor cells have evolved countermeasures to evade immune surveillance and strike back by modulating immune checkpoint related pathways. At present, monoclonal antibody drugs targeting checkpoints like PD-1 and CTLA-4 have significantly prolonged the survival of a variety of cancer patients, and thus have marked a great achievement in the history of antitumor therapy. Nevertheless, this is not the end of the story. As the relationship between genomic alteration and checkpoint expression is being delineated though the advances of preclinical animal models and emerging technologies, novel checkpoint targets are on the way to be discovered.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Descoberta de Drogas , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo
17.
Am J Respir Cell Mol Biol ; 62(6): 767-782, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32048861

RESUMO

Pneumocystis is an unusual, opportunistic fungal pathogen capable of causing Pneumocystis pneumonia (PCP) in immunocompromised hosts. Although PCP was discovered >100 years ago, its pathogenesis remains unclear. The inhibitory receptor PD-1 (programmed death 1), a negative regulator of activated T cells, has been reported to take part in tumor escape, immune tolerance, and infection immunity. In this study, we examined the role of the PD-1/PD-L1 (programmed death-ligand 1) pathway in patients with PCP and in mice. The expression levels of PD-1/PD-L1 in patients with PCP and in mice were measured by real-time PCR and flow cytometry. The effects of PD-1 deficiency are demonstrated using wild-type and PD-1-/- mice. Our data show that Pneumocystis infection promotes PD-1/PD-L1 expression; PD-1 deficiency enhances the phagocytic function of macrophages and the pulmonary T-helper cell type 1 (Th1)/Th17 response, which might contribute to Pneumocystis clearance; and PD-1 deficiency affects the polarization of macrophages. PCP mice treated with anti-PD-1 antibody showed improved pulmonary clearance of Pneumocystis. Collectively, our results demonstrate that the PD-1/PD-L1 pathway plays a role in regulating the innate and adaptive immune responses, suggesting that manipulation of this pathway may constitute an immunotherapeutic strategy for PCP.


Assuntos
Antígeno B7-H1/fisiologia , Ativação de Macrófagos/fisiologia , Pneumonia por Pneumocystis/imunologia , Receptor de Morte Celular Programada 1/deficiência , Células Th1/imunologia , Células Th17/imunologia , Imunidade Adaptativa , Adulto , Idoso , Animais , Anticorpos Antifúngicos/sangue , Antígeno B7-H1/biossíntese , Antígeno B7-H1/genética , Feminino , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido , Imunoterapia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Infecções Oportunistas/imunologia , Pneumocystis/imunologia , Pneumonia por Pneumocystis/genética , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
18.
Proc Natl Acad Sci U S A ; 117(8): 4292-4299, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32034098

RESUMO

The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice. This was in contrast to parabionts between mice that had undergone an acute LCMV infection where virus-specific CD8 T cells established equilibrium demonstrating circulation of memory T cells generated after viral clearance. We have identified a population of PD-1+ TCF1+CXCR5+Tim-3- stemlike virus-specific CD8 T cells that reside in lymphoid tissues and act as resource cells for maintaining the T cell response during chronic infection. These are the cells that proliferate and give rise to the more terminally differentiated PD-1+ CXCR5-Tim-3+ CD8 T cells. Both the stemlike CD8 T cells and their terminally differentiated progeny showed minimal migration during chronic infection and the few LCMV-specific CD8 T cells that were present in circulation were the recently emerging progeny from the stemlike CD8 T cells. The PD-1+ TCF1+CXCR5+ stemlike CD8 T cells were truly resident in lymphoid tissues and did not circulate in the blood. We propose that this residency in specialized niches within lymphoid tissues is a key aspect of their biology and is essential for maintaining their quiescence and stemlike program under conditions of a chronic viral infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Tecido Linfoide/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Feminino , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Memória Imunológica , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/genética , Tecido Linfoide/virologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/genética , Receptores CXCR5/genética , Receptores CXCR5/imunologia
19.
Asia Pac J Clin Oncol ; 16(3): 137-141, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32030888

RESUMO

AIM: To characterize the distribution of T cell immunoglobulin mucin-domain-containing-3 (Tim-3) within the exhausted T cells in patients with newly diagnosed acute myeloid leukemia (AML) and AML in complete remission. METHODS: Tim-3 expression and coexpression with PD-1, CD244, and CD57 in CD3+, CD4+, and CD8+T cells were analyzed by multicolored fluorescent flow cytometry in peripheral blood from 28 newly diagnosed, untreated AML patient and 12 cases with AML in complete remission, 23 healthy individuals served as control. RESULTS: Increasing Tim-3+CD244+ and Tim-3+CD57+ in CD3+, CD4+, and CD8+ T cells were found in AML and AML-CR groups in comparison with healthy controls. Similarly, increasing Tim-3 coexpression PD-1+ CD3+/CD4+/CD8+ T cells were found in AML group. A high tendency of PD-1+Tim-3+CD3+/CD4+/CD8+ T cells was detected in the AML-M4 subtype group followed by the M2 group, and a low tendency was found in the M3 group. Moreover, Tim-3+CD244+CD8+ T cells were found to be significantly higher in the M4 than that in M3 group. Dynamic changes of Tim-3+ T cells in AML patients who achieved CR after chemotherapy at different time points showed that Tim-3+ T cell subsets were evidently decreased; however, they remained at a higher level in most AML-CR patients. CONCLUSION: We made a novel observation on distribution of Tim-3+CD244+, Tim-3+CD57+, and Tim-3+PD-1+ T cells in patients with AML. Chemotherapy is incapable of resolving immunosuppression in some cases with AML in CR status.


Assuntos
Antígenos CD57/genética , Leucemia Mieloide Aguda/genética , Receptor de Morte Celular Programada 1/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Science ; 367(6481)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32029687

RESUMO

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRß (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.


Assuntos
Transferência Adotiva , Sistemas CRISPR-Cas , Edição de Genes , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia , Linfócitos T/transplante , Idoso , Proteína 9 Associada à CRISPR , Engenharia Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Transgenes
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