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1.
Cancer Treat Rev ; 79: 101887, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491661

RESUMO

Small cell lung cancer (SCLC) was defined as a "recalcitrant cancer" because of its dismal prognosis and lack of outcome improvements in the last 30 years. Immunotherapy with checkpoint inhibitors revolutionized treatment in many cancer types and results from the IMpower133 study, a double-blind placebo-controlled phase III trial, showed overall survival benefit for atezolizumab when added to standard platinum-etoposide chemotherapy in first-line SCLC setting for the first time since years. Trials with other checkpoint inhibitors, e.g. pembrolizumab, durvalumab, nivolumab and ipilimumab, are ongoing in various settings, but, to date, there are no defined factors to identify patients who are more likely to benefit from such treatments. This review summarizes results of immunotherapy trials in SCLC for first-line, maintenance and further-line therapies for single-agents and combinations with checkpoint inhibitors. Predictive factors from these trials are reviewed in order to identify their clinical value, with particular emphasis on PD-L1 expression on both tumor cells and in stroma, especially in pembrolizumab-treated patients, and tumor mutational burden, for patients treated with the ipilimumab and nivolumab combination.


Assuntos
Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Imunomodulação/efeitos dos fármacos , Imunoterapia/métodos , Imunoterapia/tendências , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento
2.
Pol J Pathol ; 70(2): 109-114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556561

RESUMO

Our aim was to analyzed the significance of CD11c and CD123 positive DCs and their relations with some clinical and pathologic parameters of patients with non-small cell lung cancer (NSCLC). The immunohistochemical expression of CD11c and CD123, was evaluated in 40 patients with NSCLC. After analysis we found that 35.3% of the patients in the T3-4 tumour stage had a high CD11c infiltration in the tumour stroma, while 100% of the patients in the T1-2 tumour stage had low infiltration (p = 0.03). We also found that 71.4% of patients in the M1 stage had a high infiltration with CD123 in the tumour stroma, whereas only 15.6% of patients without metastases had high infiltration, analogous data are also found in comparing the distribution of CD123 in the tumour border (p = 0.002 or p = 0.002). Comparing the density of CD123 in the border of lymph node involvement, we found that only 7.14% of patients without metastases had low infiltration with dendritic cells, whereas in patients with metastatic lymph nodes that percentage was 41.7% (p = 0.008). In conclusion results suggest that CD11c- and CD123-positive DCs play an important role in antitumour immunity and can be predictive factor for tumour development in patients with NSCLC.


Assuntos
Antígeno CD11c/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Neoplasias Pulmonares/imunologia , Células Dendríticas , Humanos , Estadiamento de Neoplasias
3.
Cancer Immunol Immunother ; 68(9): 1501-1513, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31489465

RESUMO

INTRODUCTION: Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis. METHODS: Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation. RESULTS: Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression. CONCLUSIONS: The frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.


Assuntos
Neoplasias Encefálicas/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/secundário , Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Células Cultivadas , ELISPOT , Feminino , Citometria de Fluxo , Humanos , Tolerância Imunológica , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Regulação para Cima
4.
Anticancer Res ; 39(9): 4987-4993, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519605

RESUMO

BACKGROUND/AIM: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment. PATIENTS AND METHODS: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history. RESULTS: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients. CONCLUSION: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Docetaxel/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
5.
Cancer Immunol Immunother ; 68(10): 1585-1596, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31515670

RESUMO

Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline samples, discriminant analysis revealed a combination of four variables that helped differentiate stable disease-response (SD-R) from progressive disease (PD) patients: augmented frequency of central memory CD4+ T cells and leukocyte count was associated with response while increased percentage of PD-L1+ natural killer cells and naïve CD4+ T cells was associated with lack of response. After therapy, differential changes between responders and non-responders were found in leukocytes, T cells and TIM-3+ T cells. Patients with progressive disease showed an increase in the frequency of TIM-3 expressing CD4+ and CD8+ T cells, whereas SD-R patients showed a decrease in these subsets. Our findings indicate that a combination of immune variables from peripheral blood (PB) could be useful to distinguish response groups in NSCLC and RCC patients treated with anti-PD-1 therapy. Frequency of TIM-3+ T cells showed differential changes after treatment in PD vs SD-R patients, suggesting that it may be an interesting marker for monitoring progression during therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Idoso , Proteína C-Reativa/análise , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Renais/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A/sangue , Humanos , Neoplasias Renais/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade
6.
Anticancer Res ; 39(8): 4517-4523, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366554

RESUMO

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have dramatically changed the clinical outcomes of advanced tumours. However, biomarkers for monitoring immunological features during immunotherapy remain unclear, especially those in the peripheral blood, which are easily available. This study evaluated the usefulness of nCounter Analysis System in identifying immunological biomarkers in peripheral blood mononuclear cells (PBMCs) during ICI therapy. PATIENTS AND METHODS: PBMCs from two patients who responded well to ICI therapy were used, and the expression levels of immune-related mRNA and extracellular proteins were analyzed. RESULTS: Changes in the expression levels of 55 genes from pre-treatment to on-treatment were bioinformatically similar between the two cases. The expression levels of PD-1 were consistent with those by flow cytometry analysis, a reliable tool for monitoring various markers. CONCLUSION: The nCounter Analysis System may be a potent tool to simultaneously investigate genes and proteins on PBMCs as biomarkers during immunotherapy using a small amount of sample.


Assuntos
Biomarcadores Tumorais/sangue , Imunoterapia , Neoplasias Pulmonares/sangue , Proteínas de Neoplasias/genética , Idoso , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue
7.
Medicine (Baltimore) ; 98(33): e16875, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415428

RESUMO

EGFR-TKIs have been widely used in the first-line treatment of NSCLC patients harboring EGFR mutations. However, the prognosis indicators are limited. In the present study, the prognostic value of systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) were assessed in EGFR-Mutant lung adenocarcinoma patients treated with first-generation EGFR-TKIs. Two hundred three patients were included in this retrospective analysis. SII was calculated as platelet counts × neutrophil counts / lymphocyte counts. Receiver operating characteristic (ROC) curve was used to evaluate the optimal cut-off value for SII, NLR, and PLR. Univariate and multivariate survival analysis were performed to identify factors correlated with PFS and OS. Applying cut-offs of ≥1066.935 (SII), ≥4.40 (NLR), and ≥182.595 (PLR), higher NLR was associated with worse Eastern Cooperative Oncology Group performance status (ECOG PS) (P = .006), and higher brain metastasis rate (P = .03), higher PLR was associated with smoking history (P = .037), and worse ECOG PS (P = .001), and higher SII groups were associated with worse ECOG PS (P = .002). In univariate analysis, higher NLR (P < .001), higher PLR (P = .002), and higher SII (P < .001) were associated with worse PFS. Higher NLR (P < .001), and higher SII (P < .001) were associated with worse OS. In multivariate analysis, NLR (HR 1.736;95%CI:1.020-2.954; P = .03), PLR (HR 1.823; 95%CI:1.059-3.137; P = .04), and SII (HR2.577; 95%CI:1.677-3.958; P < .001) were independently correlated with PFS. While only SII (HR 2.802; 95%CI:1.659-4.733; P < .001) was independently correlated with OS. The present study demonstrated that SII is an independent prognostic factor for poor survival of advanced EGFR-Mutant lung adenocarcinoma patients treated with first-generation TKIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/uso terapêutico , Feminino , Humanos , Inflamação/patologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Sensibilidade e Especificidade
8.
Cancer Sci ; 110(10): 3244-3254, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368625

RESUMO

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) as first-line treatment in 70 patients with advanced EGFR-mutant non-small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28-8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death-1 ligand-1 (PD-L1), as high (50% or more) or low (less than 50%), and ligand-2 (PD-L2) expression, respectively. The extent of CD8+ tumor-infiltrating lymphocytes was evaluated on a scale of 0-3, with 0-1 as low and 2-3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD-L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD-L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression-free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR-TKIs differed according to the TME, and the phenotype with high PD-L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.


Assuntos
Antígeno B7-H1/metabolismo , Antígenos CD8/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Receptores ErbB/genética , Feminino , Humanos , Japão , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
9.
Life Sci ; 233: 116713, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386875

RESUMO

Lung cancer is the leading cause of cancer-related mortality worldwide. Treatment with immunotherapy has made a significant impact on the outcomes for those patients suffering from lung cancer and its usage is currently an established treatment modality. Immune checkpoint inhibition that has blocking antibodies which target cytotoxic T-lymphocyte antigen-4 (CTLA-4) along with the programmed cell death protein 1 (PD-1) pathway [programmed death - 1/programmed death-ligand 1 (PD-L1)] have shown promising results for numerous malignancies. Nivolumab and pembrolizumab have been approved as PD-1 blocking antibodies while atezolizumab, avelumab, and durvalumab are approved as PD-L1 blocking antibodies by 'US Food and Drug Administration'. Immune checkpoint inhibitors have been found to statistically improve the survival of patients with lung cancer and have emerged as the primary immunotherapy in lung cancer and have changed the treatment paradigm for advanced disease. Despite such benefits, treatment with immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse effects or side effects. Also, resistance is routinely developing in patients treated with immune checkpoint inhibitors. The current review provides an overview of immune checkpoint inhibitor treatment in lung cancer, its resistance, and adverse effects.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Prognóstico
10.
Cancer Immunol Immunother ; 68(9): 1429-1441, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31428800

RESUMO

MHC class I-related chain A (MICA) is one of the major ligands for natural killer group 2 member D (NKG2D), which is an activating NK receptor. MICA is expressed on the surface of human epithelial tumor cells, and its shedding from tumor cells leads to immunosuppression. To activate immune response in the tumor microenvironment, we designed an anti-VEGFR2-MICA bispecific antibody (JZC01), consisting of MICA and an anti-VEGFR2 single chain antibody fragment (JZC00) and explored its potential anti-tumor activity. JZC01 targeted vascular endothelial growth factor receptor 2 (VEGFR2) and inhibited tumorigenesis by blocking the VEGFR2 signaling pathway. Additionally, JZC01 promoted NK and CD8+ T cells to release IFN-γ and engaged activated lymphocytes to lysis of VEGFR2-expressing tumor cells. The in vivo anti-tumor activity of JZC01 was investigated by establishing a Lewis lung cancer cell-transplanted mouse model. It effectively reduced the tumor vascular density and increased the infiltration and activation of NK and CD8+ T cells in the tumor microenvironment. Thus, JZC01 functions in anti-tumor angiogenesis and anti-tumor immune activation, and showed improved anti-tumor efficacy combined with docetaxel, which provides a new insight into anti-tumor therapy.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Animais , Anticorpos Biespecíficos/genética , Apoptose , Carcinoma Pulmonar de Lewis , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Interferon gama/metabolismo , Neoplasias Pulmonares/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
11.
Scand J Immunol ; 90(3): e12802, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31269269

RESUMO

Glucose and nutrient uptake is essential in supporting T cell activation and is increased upon CD3/CD28 stimulation. As T cells from pleural effusions secondary to lung cancer show impaired function, we hypothesized that these cells might have altered expression of nutrient transporters. Here, we analysed by flow cytometry the expression of the transferrin receptor CD71, amino acid transporter CD98 and glucose transporter Glut1 and glucose uptake in pleural effusion-derived T cells from lung cancer patients, after stimulation via CD3/CD28 under normoxia or hypoxia (2% O2 ). We compared the response of T cells from pleural effusions secondary to lung cancer with that of T cells from nonmalignant effusions. In memory T cells from both groups, anti-CD3/CD28-stimulation under normoxia upregulated CD98 and CD71 expression (measured as median fluorescence intensity, MFI) in comparison with anti-CD3-stimulation. Costimulation under hypoxia tended to increase CD98 expression compared to CD3-stimulation in memory T cells from both groups. Remarkably, in the cancer group, memory T cells stimulated via CD3/CD28 under hypoxia failed to increase CD71 and Glut1 expression levels compared to the cells receiving anti-CD3 stimulation, a phenomenon that contrasted with the behaviour of memory T cells from nonmalignant effusions. Consequently, glucose uptake by memory T cells from the cancer group was not increased after CD3/CD28 stimulation under hypoxia, implying that their glycolytic metabolism is defective. As this process is required for inducing an antitumoural response, our study suggests that memory T cells are rendered dysfunctional and are unable to eliminate lung tumour cells.


Assuntos
Antígenos CD28/metabolismo , Complexo CD3/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Memória Imunológica/imunologia , Neoplasias Pulmonares/metabolismo , Derrame Pleural/metabolismo , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Linfócitos T/metabolismo
12.
Chem Commun (Camb) ; 55(68): 10060-10063, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31328750
14.
Cancer Sci ; 110(9): 2711-2721, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31294893

RESUMO

The percentage of programmed death ligand 1 (PD-L1) positivity in cancer cells, named as the tumor proportion score, is considered to be a predictive biomarker for anti-PD-1/PD-L1 therapy in lung cancer. PD-L1 is expressed on not only cancer cells but also on immune cells, including macrophages. Although previous studies related to PD-L1/2 expression in cancer tissues have been generally based on single immunohistochemistry (IHC), in the present study, we attempted to evaluate accurate PD-L1/2 expression in cancer cells in lung adenocarcinoma cells using double IHC to also evaluate macrophages. Of the 231 patients, PD-L1 expression was negative in 169 patients (73.2%), 1%-49% positive in 47 patients (20.3%), and ≥50% positive in 15 patients (6.5%). Interestingly, PD-L1 positivity was decreased when using double IHC compared with the estimation by single IHC. High PD-L1 expression was associated with high-grade cancer cells and in higher stage cancer. PD-L2 was negative in 109 patients (47.2%), 1%-49% positive in 50 patients (21.6%), and ≥50% positive in 72 patients (31.2%). The number of PD-L2-positive patients was increased in cases that had an epidermal growth factor receptor (EGFR) mutation and in lower stage cancer. Thirty-five patients (15.2%) were positive for both PD-L1 and PD-L2, whereas 81 patients (35.1%) were negative for both PD-L1 and PD-L2. Log-rank analysis showed that progression-free survival and overall survival were significantly the longest in the PD-L1-negative and PD-L2-positive groups (P < .0001 and P = .0120). We observed lower PD-L1 or PD-L2 expression in lung adenocarcinoma than previously reported. Double IHC for macrophages may help clinicians to evaluate PD-L1 or PD-L2 expression specifically in cancer cells.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/análise , Neoplasias Pulmonares/patologia , Proteína 2 Ligante de Morte Celular Programada 1/análise , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica/métodos , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Resultado do Tratamento
15.
Cancer Sci ; 110(8): 2348-2356, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222843

RESUMO

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non-small-cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA-4/PD-1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log-rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06-0.50], P < .001). The association with progression-free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD-L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12-0.75], P = .010). Combined high TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8+ T cells and natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, the PTEN mutation was only found in non-responders (Fisher's exact test, all P < .05). These findings may be applicable for guiding immunotherapy for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Imunidade/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunidade/imunologia , Memória Imunológica/genética , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/imunologia , Intervalo Livre de Progressão , Linfócitos T Reguladores/imunologia , Carga Tumoral/genética , Carga Tumoral/imunologia
16.
Oncology ; 97(4): 228-235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216560

RESUMO

BACKGROUND: Immuno-oncological (IO) therapies such as PD-1 and PD-L1 antibodies have been introduced in the treatment of advanced non-small cell lung cancer (NSCLC) since 2015 based on randomized trials showing unprecedented advantages in overall survival (OS) with hazard ratios (HRs) between 0.5 and 0.7. The impact of these treatments on OS in routine clinical practice and the role of tumor mass have not been studied. METHODS: 557 consecutive patients with inoperable stage III or stage IV NSCLC diagnosed in our certified lung cancer center from 2006 to 2018 were included if they had received at least one line of systemic treatment. OS of immuno-oncologically treated patients (IO patients, n = 144) who received treatment with a PD-1 antibody (nivolumab [n = 77] or pembrolizumab [n = 51]) or a PD-L1 antibody (atezolizumab [n = 4] or durvalumab [n = 12]) was compared to historic controls treated before availability of IO treatment (n = 413) using case-control analysis. IO patients and historic controls were individually matched for stage, performance state, histology, smoking status, gender, age, and initial treatment mode (palliative vs. definitive radio-chemotherapy). RESULTS: Case-control analysis of 91 matched pairs showed significantly longer OS in IO patients compared to historic controls (21.2 vs. 10.9 months, HR 0.526, CI 0.373-0.723). The benefit was more pronounced in patients with lower tumor stage (HR 0.48 [stage III], 0.40 [IVA], 0.63 [IVB]) or smaller tumor size (HR 0.38 [RECIST ≤57 mm], 0.40 [RECIST 58-94 mm], 0.59 [RECIST 95-141 mm], 0.75 [RECIST ≥142 mm]). CONCLUSIONS: IO patients showed significant benefit in OS with HRs comparable to those reported in phase III trials. The benefit tended to be greater in patients with lower tumor mass.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
17.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052488

RESUMO

Background: Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in order to assess the safety and efficacy of SABR-ICI combination. Material and Methods: MEDLINE databases from 2009 to March 3, 2019 were reviewed to obtain English language studies reporting clinical outcomes of the combination of ICI-SABR in NSCLC. 18 out of the 429 initial results fulfilled the inclusion criteria and were selected for review. Results: Eighteen articles, including six prospective studies, describing 1736 patients treated with an ICI-SABR combination fulfilled the selection criteria. The reported mean rates for local control and distant/abscopal response rates were 71% and 41%, respectively. Eleven studies reported progression-free survival and overall survival, with a mean of 4.6 and 12.4 months, respectively. Toxicity rates were consistent with the ones attributable to ICI treatment alone. Conclusions: The ICI-SABR combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than SABR alone, with a relevant impact on PFS. More studies are needed to improve patient selection for an optimal benefit from this approach.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Metástase Neoplásica/radioterapia , Metástase Neoplásica/terapia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada/métodos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Radiocirurgia/métodos , Resultado do Tratamento
18.
J Immunol Res ; 2019: 7596786, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049360

RESUMO

Type I interferon (IFN-I) plays a critical role in the antitumor immune response. In our previous study, we showed that IFN-I-inducible 2'-5' oligoadenylate synthetase-like 1 (OASL1) negatively regulated IFN-I production upon tumor challenge similar to that of viral infection. Thus, OASL1-deficient (Oasl1 -/-) mice were more resistant to implanted tumor growth than wild-type (WT) mice. In this study, we investigated whether targeting or suppressing OASL1 could show synergistic effects on tumor clearance with conventional cancer therapies (such as chemotherapy and radiotherapy) using Oasl1 -/- mice and a transplantable lung metastatic tumor cell model. Upon treatment with the anticancer drug cisplatin, we found that Oasl1 -/- mice showed enhanced resistance to injected tumors compared to untreated Oasl1 -/- mice. Similarly, irradiated Oasl1 -/- mice showed better resistance to tumor challenge than untreated Oasl1 -/- mice. Additionally, we found that Oasl1 -/- mice applied with both types of the cancer therapies contained more cytotoxic effector cells, such as CD8+ T cells and NK cells, and produced more cytotoxic effector cytokine IFN-γ as well as IFN-I in their tumor-containing lungs compared to untreated Oasl1 -/- mice. Collectively, these results show that targeting OASL1 together with conventional cancer therapies could be an effective strategy to enhance treatment efficacy.


Assuntos
2',5'-Oligoadenilato Sintetase/antagonistas & inibidores , Cisplatino/uso terapêutico , Interferon Tipo I/imunologia , Neoplasias Pulmonares/imunologia , 2',5'-Oligoadenilato Sintetase/genética , Animais , Antineoplásicos , Interferon gama/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Metástase Neoplásica
19.
Cancer Sci ; 110(7): 2100-2109, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100180

RESUMO

The presence of interleukin (IL)-17-producing T cells has recently been reported in non-small cell lung cancer (NSCLC) patients. However, the long-term prognostic significance of these populations in NSCLC patients remains unknown. In the present study, we collected peripheral blood from 82 NSCLC patients and 22 normal healthy donors (NC). Percentages of IL-17-producing CD4+ T (Th17), CD8+ T (Tc17) and γδT cells (γδT17) were measured to determine their association with clinical outcomes and overall survival (OS) in NSCLC. All NSCLC patients were followed up until July 2018. Median follow-up time was 13.5 months (range 1-87 months). The 3- and 5-year survival rate was 27% and 19.6%, respectively. We found that Th17 cells and γδT17 cells were significantly increased, whereas Tc17 cells were markedly decreased in patients with NSCLC compared with those in NC. In addition, Th17 cells were significantly positively associated with T helper type 1 cells (Th1), whereas γδT17 cells were significantly negatively associated with γδT + interferon (IFN)-γ+ cells. High percentages of peripheral Tc17 cells were significantly associated with favorable 5-year OS (P = .025), especially in patients with early TNM stage (P = .016). Furthermore, high percentages of peripheral Th17 cells were positively associated with favorable 5-year OS in patients with late TNM stage (P = .002). However, no significant association was observed between γδT17 cells and OS, regardless of the TNM stage. In conclusion, our findings suggest that enhanced Th17 and reduced Tc17 cells in the peripheral blood could be a significant predictor of a favorable prognosis for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Interleucina-17/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos T/citologia , Células Th17/citologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Interferon gama/metabolismo , Linfócitos Intraepiteliais/citologia , Linfócitos Intraepiteliais/imunologia , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Linfócitos T/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th17/imunologia
20.
Virchows Arch ; 475(1): 67-76, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127385

RESUMO

With the approval of pembrolizumab for first- and second-line treatment of PD-L1+ non-small cell lung cancer (NSCLC), PD-L1 testing by immunohistochemistry (IHC) has become a necessity. However, the DAKO autostainer ASL48 for the FDA approved DAKO 22C3 pharmDx assay is not broadly available in Switzerland and other parts of Europe. The primary goal of this study was to cross-validate the 22C3 anti-PD-L1 antibody on Benchmark Ultra (VBMU) and Leica Bond (LBO) immunostainers. IHC protocols were developed for 22C3 on both platforms with the 22C3phDx using ASL48 as reference. A tissue microarray (TMA) was constructed from 23 NSCLC specimens with a range of PD-L1 staining results. Empty TMA sections and the 22C3 antibody were distributed to 16 participants for staining on VBMU (8 centers) and/or LBO (12 centers) using the centrally developed protocols. Additionally the performance of the Ventana SP263 assay was tested in five centers. IHC scoring was performed centrally. Categorical PD-L1 staining (0-49% vs. 50-100%) did not significantly differ between centers using VBMU, whereas data from LBO were highly variable (p < 0.001). The SP263 assay was well concordant with 22C3 on VBMU and with 22C3 pharmDx. PD-L1 IHC using a standardized 22C3 protocol on VBMU provides satisfactory results in most centers. The SP263 assay is confirmed as a valid alternative to 22C3 pharmDx. 22C3 PD-L1 IHC on LBO shows major staining variability between centers, highlighting the need for local validation and adjustment of protocols.


Assuntos
Anticorpos/imunologia , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/química , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/química , Automação Laboratorial , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imuno-Histoquímica/instrumentação , Imuno-Histoquímica/normas , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Suíça , Análise Serial de Tecidos
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