RESUMO
BACKGROUND: Radiotherapy is a highly effective treatment for cervical cancer. Recent studies focused on the radiotherapy induced anti-tumor immunity. Whether tumor-derived extracellular vesicles (EVs) play roles in radiotherapy induced tumor associated macrophage (TAM) polarization remains unclear. MATERIALS AND METHODS: This study analysed the phenotype of macrophages in cancer tissue and peripheral blood of cervical cancer patients using flow cytometry analysis. The role of EVs from plasma of post-irradiated patients on M2-like transformed macrophages was assessed. The M1- and M2-like macrophages were assessed by expression of cell surface markers (CCR7, CD163) and intracellular cytokines (IL-10, TNFα and iNOS). The capacity of phagocytosis was assessed by PD-1 expression and phagocytosis of pHrodo Red E. coli bioparticles. RESULTS: Our results demonstrated that radiotherapy of cervical cancer induced an increase in the number of TAMs and a change in their subtype from the M2-like to the M1-like phenotype (increased expression of CCR7 and decreased expression of CD163). The EVs from plasma of post-irradiated patients facilitated the M2-like to the M1-like phenotype transition (increased expression of CCR7, TNFα and iNOS, and decreased expression of CD163 and IL-10) and increased capacity of phagocytosis (decreased PD-1 expression and increased phagocytosis of pHrodo Red E. coli bioparticles). CONCLUSIONS: Our data demonstrated that irradiation in cervical cancer patients facilitated a proinflammatory macrophage phenotype which could eventually able to mediate anti-tumor immune responses. Our findings highlight the importance of EV in the crosstalk of tumor cells and TAM upon irradiation, which potentially leading to an increased inflammatory response to cancer lesions.
Assuntos
Anticorpos Antineoplásicos/efeitos da radiação , Vesículas Extracelulares/efeitos da radiação , Imunidade/efeitos da radiação , Macrófagos Associados a Tumor/efeitos da radiação , Neoplasias do Colo do Útero/radioterapia , Adulto , Braquiterapia , Citocinas/efeitos da radiação , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Neoplasias do Colo do Útero/imunologiaRESUMO
The aim of this study was to investigate the associations between secondary mutations of c-KIT/PDGFRα and acquired imatinib resistance or efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors (GISTs). Mutations of c-KIT (exons 9, 11, 13, 14, 17, and 18) and PDGFRα (exons 12 and 18) in tumor samples of 50 patients were analyzed by direct sequencing. A total of 50 samples before imatinib and 52 samples after imatinib were collected. Among 52 samples after imatinib, 38 samples were imatinib resistant and 14 samples were imatinib sensitive. All patients before imatinib treatment had primary mutations of c-KIT exon 11 (n = 45) or exon 9 (n = 5), and no PDGFRα mutations were found in these patients. After imatinib treatment, 25 of 38 (65.8 %) resistant tumors had secondary mutations in c-KIT exon 13 (n = 10), exon 14 (n = 1), exon 17 (n = 12) and exon 18 (n = 2), while no secondary mutations of c-KIT were found in 14 sensitive tumors (P < 0.001), indicating the close association of c-KIT secondary mutations with imatinib-acquired resistance. In our study, 19 patients received sunitinib treatment after the failure of imatinib, and it seemed that the median progression-free survival (7 vs. 19 months, P = 0.244) in patients with secondary mutations (n = 13) was lower than that in patients without secondary mutations (n = 6). Secondary mutations of c-KIT were significantly associated with acquired resistance to imatinib in Chinese GIST patients, and whether secondary mutations of c-KIT could influence the efficacy of sunitinib needed to be further investigated.
Assuntos
Povo Asiático/genética , Benzamidas/uso terapêutico , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Indóis/uso terapêutico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Sequência de Aminoácidos , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação/genética , Estudos Retrospectivos , Sunitinibe , Taxa de Sobrevida/tendências , Resultado do Tratamento , Adulto JovemRESUMO
To investigate the correlation between C-KIT/PDGFRα mutations and Imatinib response or survival in Chinese advanced gastrointestinal stromal tumor (GIST) patients. Clinical data and paraffin-embedded tumor specimens were collected from 158 advanced GIST patients receiving first-line Imatinib. Mutation analyses of C-KIT gene (Exons 9, 11, 13, and 17) and PDGFRα gene (exons 12 and 18) were performed by PCR amplification and Sanger sequencing. A total of 135 patients harboring C-KIT mutations (exon 11 mutation: 108; exon 9 mutation: 23; exon 13 mutation: 2; exon 17 mutation: 2) and one patients carrying PDGFRα mutation (exon 18) were found in this study. Twenty-two patients (13.9 %) with neither C-KIT nor PDGFRα mutations were named as wild type. The response rate (64.7 vs. 36.4 %, P = 0.000) and median progression-free survival (28 vs. 8 months, P = 0.000) of mutant patients (n = 136) were significantly higher than those of wild-type patients (n = 22). Moreover, the response rate and median progression-free survival in patients with exon 11 mutations (n = 108), exon 9 mutations (n = 23), and wild-type patients (n = 22) were 68.5, 47.8, and 36.4 % (P = 0.001), and 31 months, 13 months, and 8 months (P = 0.000), respectively. No significant differences of response rate or median progression-free survival were seen in patients with exon 11 deletion mutations, point mutations, and mixed-type mutations. C-KIT mutations were closely associated with Imatinib response and progression-free survival of Chinese advanced GIST patients. Other predictive markers for Imatinib would be further investigated.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/genética , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Adulto , Idoso , Povo Asiático , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
AIM: To investigate the efficacy and safety of imatinib dose escalation in Chinese patients with advanced gastrointestinal stromal tumor (GIST). METHODS: Advanced GIST patients previously failing 400 mg imatinib treatment were enrolled in this study. Patients received imatinib with dose escalation to 600 mg/d, and further dose escalation to 800 mg/d if imatinib 600 mg/d failed. Progression-free survival, overall survival, clinical efficacy, c-kit/PDGFRA genotype and safety were evaluated. RESULTS: 52 patients were enrolled in this study. For the 47 evaluable patients receiving imatinib (600 mg/d), the disease control rate was 40.4%, and the median progression-free survival for all patients was 17 wk (95% CI: 3.9-30.1). The median overall survival after dose escalation was 81 wk (95% CI: 36.2-125.8). Adverse events, mainly edema, fatigue, granulocytopenia and skin rash were tolerable. However, further dose escalation (800 mg/d) in 14 cases was ineffective, with disease progression and severe adverse events. Among 30 cases examined for gene mutations, patients with exon 9 mutations experienced a better progression-free survival of 47 wk. CONCLUSION: Imatinib dose escalation to 600 mg/d is more appropriate for Chinese patients and may achieve further survival benefit.