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1.
Lung Cancer ; 180: 107219, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37146474

RESUMO

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.


Assuntos
Inibidores da Angiogênese , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Indóis , Mesotelioma Maligno , Receptor de Morte Celular Programada 1 , Inibidores de Proteínas Quinases , Humanos , Feminino , Animais , Camundongos , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Mesotelioma Maligno/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Indóis/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Aloenxertos
2.
Cancer Sci ; 111(8): 2895-2906, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32530527

RESUMO

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1ß in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1ß, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1ß/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).


Assuntos
Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Mesotelioma Maligno/patologia , Pleura/patologia , Receptores Tipo I de Interleucina-1/metabolismo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Amianto/toxicidade , Biópsia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Humanos , Inflamassomos/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Mesotelioma Maligno/induzido quimicamente , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/mortalidade , Pessoa de Meia-Idade , Pemetrexede/farmacologia , Pemetrexede/uso terapêutico , Esferoides Celulares , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima
3.
Biochem Biophys Res Commun ; 519(4): 846-853, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31558317

RESUMO

Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW-II-41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Dasatinibe/farmacologia , Efrina-A2/antagonistas & inibidores , Neoplasias Pulmonares/metabolismo , Niacinamida/análogos & derivados , Carcinoma de Pequenas Células do Pulmão/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Efrina-A2/genética , Efrina-A2/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Niacinamida/farmacologia , Receptor EphA2 , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Int Immunopharmacol ; 11(6): 774-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21316504

RESUMO

Primary autoimmune neutropenia (AIN) is more common in newborns, and usually benign or self-limiting, so most cases require no specific therapy. In adults, however, for little tendency toward spontaneous remission, they require certain treatments and careful managements. Here we report a successful management of primary AIN patient by estimating the granulopoiesis according to CRP levels without administration of G-CSF or increase of prednisolone when peripheral neutrophil counts dropped down. Transient elevation of CRP associated with severe drop down in neutrophil count, and subsequent dramatic neutrophil increase was occasionally observed during the follow up with minimal dose of prednisolone. Coexistence of decreased neutrophil counts and elevated CRP levels was accompanied by increase of serum levels of IL-6 and IL-8. Although this is the report of only one patient, these elevated CRP levels combined with severe drop down and subsequently spontaneous rapid recovery in neutrophil count, were repetitively observed, suggesting the preceding CRP elevation before neutrophil recovery. We propose the important part of CRP as a predictor of granulopoiesis in patients with neutropenia.


Assuntos
Doenças Autoimunes/diagnóstico , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Neutropenia/diagnóstico , Neutrófilos/patologia , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Proteína C-Reativa/genética , Contagem de Células , Feminino , Humanos , Interleucina-6/sangue , Interleucina-8/sangue , Pessoa de Meia-Idade , Neutropenia/patologia , Neutropenia/fisiopatologia , Prognóstico
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