RESUMEN
Cryoablation is a therapeutic modality for lung adenocarcinoma that destroys target tumors using lethal levels of cold, resulting in the release of large amounts of specific antigens that activate immune responses. However, tumor immune checkpoint escape mechanisms prevent these released self-antigens from inducing effective anti-tumor immune responses. To overcome this challenge, we propose the use of immune checkpoint inhibitors to relieve T cell inhibition by immune checkpoints and enhance the anti-tumor immune response mediated by cryoablation. We used bilateral tumor-bearing mouse models and a specific cryoablation instrument to study the efficacy of cryoablation combined with PD-1 inhibitors in Lewis lung adenocarcinoma model mice. We found that cryoablation combined with PD-1 inhibitors significantly inhibited the growth of mouse lung adenocarcinoma, prolonged mouse survival, and enhanced the anti-tumor immune response. Moreover, this combined regimen could synergistically promote the activation and proliferation of T cells via the PI3K/AKT/mTOR pathway. The present study provides a strong theoretical basis for the clinical combination of cryoablation and PD-1 inhibitors.
Asunto(s)
Carcinoma Pulmonar de Lewis , Criocirugía , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Fosfatidilinositol 3-Quinasas , Receptor de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Criocirugía/métodos , Ratones , Carcinoma Pulmonar de Lewis/inmunología , Carcinoma Pulmonar de Lewis/patología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Transducción de Señal/efectos de los fármacos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Ratones Endogámicos C57BL , Línea Celular Tumoral , Terapia Combinada , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Femenino , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/cirugíaRESUMEN
The effect of Epsin 3 (EPN3) on non-small cell lung cancer (NSCLC) has not yet been clearly elucidated. This study identified the exact function of EPN3 on NSCLC progression. EPN3 expression in NSCLC patients were analyzed based on the Cancer Genome Atlas database. Kaplan-Meier analysis was implemented to research the effect of EPN3 on patients' survival. EPN3 expression in clinical tissues of 62 NSCLC cases was monitored by real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry and Western blot. A549 and H1299 cells were transfected with EPN3 shRNA and treated by RO8191 (20 µM). Proliferation was researched by cell counting kit-8 and 5-ethnyl-2 deoxyuridine assays. Apoptosis was monitored by flow cytometry. Migration and invasion was assessed by Transwell experiment. EPN3 effect on A549 cell in vivo growth was researched using nude mice. RO8191 (200 µg) was intratumoral injected into mice. Immunohistochemistry and Western blot was implemented to monitor protein expression in cells and xenograft tumor tissues. EPN3 was abnormally up-regulated in NSCLC patients and cells, indicating a lower overall survival. Loss of EPN3 weakened proliferation, migration and invasion, induced apoptosis, and repressed epithelial-mesenchymal transition in NSCLC cells. Loss of EPN3 inactivated the JAK1/2-STAT3 pathway in NSCLC cells. RO8191 treatment reversed the inhibition of EPN3 knockdown on the malignant phenotype of NSCLC cells. RO8191 intratumoral injection reversed the suppression of EPN3 silencing on NSCLC cell in vivo growth. EPN3 acted as an oncogene in NSCLC via activating the JAK1/2-STAT3 pathway. EPN3 may be a promising target for NSCLC treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , MicroARNs , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Ratones Desnudos , Proliferación Celular/genética , Pulmón/patología , Línea Celular Tumoral , Movimiento Celular/genética , MicroARNs/genética , Regulación Neoplásica de la Expresión Génica , Janus Quinasa 1/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismoRESUMEN
Lung cancer is a global disease and a major cause of cancer-related mortality worldwide. Accumulated studies have confirmed the essential role of long non-coding RNAs (lncRNAs) in the occurrence and development of cancers. Meanwhile, there have been reports concerning the role of Small Nucleolar RNA Host Gene 3 (SNHG3) in various cancers. However, there are so far few studies on the function and mechanism of SNHG3 in lung cancer. In the present study, SNHG3 was found to be highly expressed in lung cancer tissues and cells. Downregulation of SNHG3 could inhibit cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process. In addition, SNHG3 was found to have the ability to bind to miR-515-5p. Furthermore, Small Ubiquitin Like Modifier 2 (SUMO2) was identified to be the downstream target of miR-515-5p, which was negatively correlated with miR-515-5p expression. SNHG3 could positively regulate SUMO2 expression by sponging miR-515-5p. In addition, the rescue experiment showed that simultaneous transfection of miR-515-5p or SUMO2 siRNA could reverse the effect of SNHG3 expression on cell proliferation and metastasis. Collectively, our study demonstrates that SNHG3 can act on miR-515-5p in the form of competitive endogenous RNA (ceRNA) to regulate SUMO2 positively and thus affect the proliferation and metastasis of NSCLC cells. Findings in our study support that SNHG3/miR-515-5p/SUMO2 regulatory axis may become a potential therapeutic target for lung cancer.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , MicroARNs/genética , ARN Largo no Codificante/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Movimiento Celular , Proliferación Celular , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Pronóstico , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
PURPOSE: Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in patients with non-small cell lung cancer (NSCLC) harboring 21-L858R mutation. PATIENTS AND METHODS: Patients with treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1) NSCLC were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125 mg, thrice daily; L858R-RD) or high-dose icotinib (250 mg, thrice daily; L858R-HD), whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee. RESULTS: From May 2015 to November 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; and 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months, respectively) and was significantly longer than that in L858R-RD group [12.9 months vs. 9.2 months, hazard ratio (HR): 0.75; 95% confidence interval (CI), 0.53-1.05]. A longer but statistically nonsignificant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI, 0.57-1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared with L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups. CONCLUSIONS: High-dose icotinib improved mPFS and ORR in patients with NSCLC harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population.