Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.455
Filtrar
1.
Gene ; 764: 145105, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32882333

RESUMO

Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Testes Genéticos/métodos , Sarcoma/mortalidade , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Mapeamento de Interação de Proteínas , Proteômica , Curva ROC , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/imunologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
2.
J Toxicol Sci ; 45(11): 701-711, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132244

RESUMO

We aimed to investigate the role of programmed cell death protein 1 (PD-1) and T lymphocytes in the proliferation, apoptosis and secretion of cells from patients and mice with Graves' disease (GD). The levels of serum hormones, related antibodies and inflammatory cytokines in GD patients were determined by electrochemiluminescence immunoassay and ELISA. The percentages of CD4 and CD8 T-lymphocytes and PD-1 expression were examined by flow cytometry. A GD mouse model, a thyroid follicular epithelial cell, and a CD4+PD-1+, CD4+PD-1- and CD8+PD-1+, CD8+PD-1- T lymphocyte co-culture system were constructed. The viability, apoptosis-related markers, serum hormones, related antibodies and inflammatory cytokines in thyroid follicular epithelial cells were determined by CCK-8, Western blot, qTR-PCR, electrochemiluminescence immunoassay and ELISA. Elevated free thyroid hormones (FT3, FT4), thyroid hormone antibodies (TRAb, TPOAb and TGAb), inflammatory cytokines, and inhibited TSH were observed in GD patients. The percentage of CD4+ T cells was increased, while that of CD8+ T cells was reduced in GD patients. PD-1 expression level was lifted in both CD4+ and CD8+ cells from GD patients. In mouse thyroid follicular epithelial cells co-cultured with CD4+PD-1+ and CD8+PD-1+ T lymphocytes, the cell viability, TH and TRAb levels and inflammatory cytokines level were the highest, while the TSH level and apoptosis were the lowest. PD-1 positive T lymphocytes were able to promote viability and inhibit apoptosis of thyroid follicular epithelial cells, which further caused a more accelerated development of GD.


Assuntos
Antígeno B7-H1/imunologia , Antígeno B7-H1/fisiologia , Proliferação de Células , Citocinas/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/fisiologia , Doença de Graves/genética , Doença de Graves/imunologia , Mediadores da Inflamação/metabolismo , Linfócitos/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/fisiologia , Glândula Tireoide/citologia , Adulto , Animais , Apoptose , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Progressão da Doença , Feminino , Doença de Graves/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade
3.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33060148

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Oncologia/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Betacoronavirus/patogenicidade , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Geografia , Humanos , Controle de Infecções/normas , Itália/epidemiologia , Masculino , Oncologia/normas , Neoplasias/imunologia , Oncologistas/estatística & dados numéricos , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Prevalência , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inquéritos e Questionários/estatística & dados numéricos , Tempo para o Tratamento
4.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33067320

RESUMO

Immune checkpoint inhibitors (ICI) block negative regulatory molecules, such as CTLA-4, PD-1 and PD-L1, in order to mount an antitumor response. T cells are important for antiviral defense, but it is not known whether patients with cancer treated with ICI are more or less vulnerable to viral infections such as COVID-19. Furthermore, immunosuppressive treatment of immune-related adverse events (irAE) may also impact infection risk. Rheumatic irAEs are often persistent, and can require long-term treatment with immunosuppressive agents. The aim of this study was to determine the incidence of COVID-19 infection and assess changes in ICI and immunosuppressive medication use among patients enrolled in a prospective rheumatic irAE registry during the height of the COVID-19 pandemic. On April 16 2020, following the 'surge' of COVID-19 infections in the New York Tri-State area, we sent a 23-question survey to 88 living patients enrolled in a single institutional registry of patients with rheumatic irAE. Questions addressed current cancer and rheumatic irAE status, ICI and immunosuppressant medication use, history of COVID-19 symptoms and/or diagnosed infection. A follow-up survey was sent out 6 weeks later. Sixty-five (74%) patients completed the survey. Mean age was 63 years, 59% were female, 70% had received anti-PD-(L)1 monotherapy and 80% had had an irAE affecting their joints. Six patients (10%) had definite or probable COVID-19, but all recovered uneventfully, including two still on ICI and on low-to-moderate dose prednisone. Of the 25 on ICI within the last 6 months, seven (28%) had their ICI held due to the pandemic. In patients on immunosuppression for irAE, none had changes made to those medications as a result of the pandemic. The incidence of COVID-19 was no higher in patients still on ICI. Ten percent of rheumatic irAE patients developed COVID-19 during the NY Tri-state 'surge' of March-April 2020. Oncologists held ICI in a quarter of the patients still on them, particularly women, those on anti-PD-(L)1 monotherapy, and those who had had a good cancer response. The incidence of COVID-19 was no higher on patients still on ICI. None of the patients on disease-modifying antirheumatic drugs or biological immunosuppressive medications developed COVID-19.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunossupressores/efeitos adversos , Neoplasias/tratamento farmacológico , Pneumonia Viral/imunologia , Doenças Reumáticas/tratamento farmacológico , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Betacoronavirus/patogenicidade , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Tomada de Decisão Clínica , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Feminino , Humanos , Incidência , Masculino , Oncologia/normas , Oncologia/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias/imunologia , Cidade de Nova Iorque/epidemiologia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricos , Doenças Reumáticas/induzido quimicamente , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/imunologia , Índice de Gravidade de Doença , Inquéritos e Questionários/estatística & dados numéricos
5.
Nat Commun ; 11(1): 5415, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110069

RESUMO

The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.


Assuntos
Anticorpos/administração & dosagem , Células Dendríticas/imunologia , Neoplasias/tratamento farmacológico , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Resistência a Medicamentos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral
7.
Oncology ; 98(11): 817-826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32892196

RESUMO

BACKGROUND: Developing personalized strategies for cancer has shown good efficacies. METHODS: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. RESULTS: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL- tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). CONCLUSIONS: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.


Assuntos
Antígeno B7-H1/biossíntese , Classe I de Fosfatidilinositol 3-Quinases/genética , Lipossarcoma/genética , Lipossarcoma/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Estudos de Coortes , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Lipossarcoma/patologia , Lipossarcoma/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Adulto Jovem
8.
J Cancer Res Ther ; 16(4): 941-945, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930148

RESUMO

Immune-checkpoint inhibitors have shown to prolong survival in patients with metastatic non-small cell lung cancer. Programmed death ligand 1 (PD-L1) expression is associated with a higher probability of response, although some patients with PD-L1 negative tumors may also respond or show durable stabilizations. However, the optimal strategy after progression to immunotherapy (IO) is not yet defined. Patients with oligometastatic disease may benefit from local treatments such as radiotherapy (RT), achieving significant local control rates. In addition, RT is claimed to have numerous immunogenic effects that could synergize with IO. We present the case of a complete responder to nivolumab that after a monotopic adrenal relapse received stereotactic body radiation therapy, followed by maintenance nivolumab achieving a partial response that is still ongoing. Aspects such as mechanisms of acquired resistance to PD-L1 inhibitors, the optimal management after progression, and the potential interplay between IO and RT are briefly reviewed and discussed.


Assuntos
Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/terapia , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Nivolumabe/uso terapêutico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Sobreviventes de Câncer , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Prognóstico , Radiocirurgia/métodos , Taxa de Sobrevida
9.
Lancet Oncol ; 21(11): 1413-1422, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32979984

RESUMO

BACKGROUND: Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC. METHODS: This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients. FINDINGS: Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4-28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9-87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three [7%]) and febrile neutropenia (three [7%]). INTERPRETATION: Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable. FUNDING: Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's Horizon 2020 research and innovation programme.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Nivolumabe/administração & dosagem , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Espanha/epidemiologia , Resultado do Tratamento
10.
Nat Commun ; 11(1): 4454, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901001

RESUMO

Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/virologia , Doença Crônica , Citotoxicidade Imunológica , Modelos Animais de Doenças , Regulação para Baixo , Tolerância Imunológica , Imunidade Celular , Técnicas In Vitro , Ativação Linfocitária , Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , RNA-Seq , Transdução de Sinais/imunologia
11.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917858

RESUMO

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
13.
Cancer Treat Rev ; 89: 102085, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32771858

RESUMO

Immune checkpoint inhibitors (ICIs) represent one of the main steps forward for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC), without oncogenic driver alterations. Despite this recent progress, only a minority of patients achieve a broad and durable benefit and another proportion report poor survival and sometimes fast disease progression, confirming the need to optimise the patient's selection. To date, several issues are unsolved about how to personalise the immunotherapy treatment for individual patients. In this review, analysing data from pivotal randomised clinical trials (RCTs), we discuss patient baseline clinical and demographic features, including sex, age, ECOG performance status, smoking habit and specific site of metastases (liver, bone and brain) that may influence the efficacy outcomes in patients treated with ICIs. The high performance of the ICIs blurred the vision on different efficacy-limiting factors, which require extensive evaluation to improve the understanding ofthe tumour-specificimmune response, in which clinical drivers could be useful for better patient stratification.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
J Virol ; 94(18)2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32641478

RESUMO

Checkpoint inhibitors are effective in restoring exhausted CD8+ T cell responses in persistent viral infections or tumors. Several compounds are in clinical use for different malignancies, but trials in patients with chronic viral infections have also been conducted. In a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, it was shown that checkpoint inhibitor treatment increased T cell proliferation and functionality, but its influence on the antigen-specific T cell receptor (TCR) repertoire is unknown. NP396-specific CD8+ T cells dominate during acute LCMV infection and are predominantly exhausted during chronic infection. Next-generation sequencing of NP396-specific TCRs showed that exhaustion corresponds with a significantly reduced NP396-specific TCR repertoire diversity: Shannon indices of 4 in immunized mice to 2.6 in persistently infected mice. Anti-PD-L1 treatment during persistent LCMV infection restored NP396-specific T cell responses and reduced viral titers. Nevertheless, anti-PD-L1-treated mice showed an even more narrowed TCR repertoire, with reduced TCR diversity compared to that of persistently infected control mice (Shannon indices of 2.1 and 2.6, respectively). Interestingly, anti-PD-L1 treatment-induced narrowing of the TCR repertoire negatively correlates with functional and physical restoration of the antigen-specific T cell response. Further, we found that private, hyperexpanded TCR clonotypes dominated the T cell response after anti-PD-L1 treatment. Although being private, these top clonotypes from anti-PD-L1-treated mice revealed a more closely related CDR3 motif than those of top clonotypes from persistently infected control mice. In conclusion, although targeting the PD-1/PD-L1 pathway reinvigorates exhausted CD8+ T cells, it fails to restore T cell repertoire diversity.IMPORTANCE Checkpoint inhibitors are effective immunotherapeutics to restore cancer- and virus-induced exhausted CD8+ T cells, by enhancing the quality and survival of immune responses. Although checkpoint inhibitors are already used as therapy against various cancers, not much is known about their multifaceted impact on the exhausted CD8+ T cell receptor (TCR) repertoire. This report describes for the first time the evolvement of an exhausted antigen-specific CD8+ TCR repertoire under checkpoint inhibitor treatment. By using a well-established virus model, we were able to show major shifts toward oligoclonality of the CD8+ TCR repertoire response against a massively exhausted lymphocytic choriomeningitis virus (LCMV) epitope. While supporting viral control in the LCMV model, oligoclonality and more private of TCR repertoires may impact future pathogenic challenges and may promote viral escape. Our results may explain the ongoing problems of viral escapes, unpredictable autoimmunity, and heterogeneous responses appearing as adverse effects of checkpoint inhibitor treatments.


Assuntos
Antígeno B7-H1/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Nucleoproteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Anticorpos Neutralizantes/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Proliferação de Células/efeitos dos fármacos , Anergia Clonal/efeitos dos fármacos , Células Clonais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Coriomeningite Linfocítica/tratamento farmacológico , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/efeitos dos fármacos , Vírus da Coriomeningite Linfocítica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nucleoproteínas/genética , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Carga Viral
15.
Oncology ; 98(11): 749-754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663833

RESUMO

Lung cancer is a leading cause of cancer death in the United States and around the world. Approximately 13% of lung cancers are small cell lung cancer (SCLC). SCLC is generally classified as a limited-stage and extensive-stage disease depending on the extent of involvement. For patients with the extensive-stage disease, until recently, chemotherapy alone has been the recommended treatment, although radiotherapy could be used in select patients for palliation of symptoms. The standard of care for extensive-stage SCLC is platinum doublet chemotherapy with either cisplatin or carboplatin in combination with etoposide. Even though first-line therapy has an initial response rate of 60-80%, the prognosis is poor, with overall survival of 10-12 months. The only FDA-approved second line of therapy is topotecan, approved both as an intravenous formulation as well as an oral formulation, with response rates of 6-12% in chemorefractory disease and 15-37% in chemosensitive disease. Immunotherapy has recently been approved as a first-line agent in metastatic SCLC in combination with chemotherapy. It is also approved as a third-line agent in metastatic SCLC after the failure of two chemotherapy regimens. The FDA approved four drugs, two of them being PD-1 inhibitors (pembrolizumab, nivolumab), and two of them being PD-L1 inhibitors (atezolizumab and durvalumab) in SCLC. This review article summarizes the significance of immunotherapy in the treatment of extensive-stage SCLC, its side effects, and limitations.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia
16.
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
17.
Nat Commun ; 11(1): 3584, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681091

RESUMO

Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer and to date, lack predictive markers. This randomized phase II study defines safety and response rate of epigenetic priming in ER-positive breast cancer patients treated with checkpoint inhibitors as primary endpoints. Secondary and exploratory endpoints included PD-L1 modulation and T-cell immune-signatures. 34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition (NCT02395627).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Imunoterapia , Linfócitos T/imunologia , Tamoxifeno/administração & dosagem , Vorinostat/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Receptores Estrogênicos/genética , Receptores Estrogênicos/imunologia , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento
18.
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
19.
PLoS One ; 15(7): e0228302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628668

RESUMO

Programmed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus (HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.


Assuntos
Antígeno B7-H1/metabolismo , Vírus da Hepatite B/imunologia , Interferon-alfa/farmacologia , Interferon gama/farmacologia , Fator de Transcrição STAT1/metabolismo , Linfócitos T/imunologia , Regulação para Cima/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/química , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Sítios de Ligação , Linhagem Celular , Hepatite B/tratamento farmacológico , Hepatite B/veterinária , Antígenos de Superfície da Hepatite B/sangue , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/metabolismo , Regiões Promotoras Genéticas , Fator de Transcrição STAT1/química , Linfócitos T/metabolismo
20.
Cancer Treat Rev ; 89: 102067, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32682248

RESUMO

BACKGROUND: Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC. METHODS: We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models. RESULTS: Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8+ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion. CONCLUSIONS: Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Microambiente Tumoral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA