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H. Yang
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-070 - Investigation of Whether HIF-1α Inhibitors Can Increase EGFR-TKI Effect for Non-Small Cell Lung Cancer Cell Lines (ID 9492)
09:30 - 09:30 | Author(s): H. Yang
- Abstract
Background:
Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in cancer progression, metastasis and angiogenesis. Activation HIF–1α pathway is also associated with epithelial growth factor receptor (EGFR) pathways. This study was to investigate whether inhibitors of HIF–1α increase the cytotoxicity of EGFR-tyrosine kinase inhibitors (TKI) on non-small cell lung cancer (NSCLC) and its mechanism.
Method:
NSCLC lines, including A549, Hcc827, Hcc827R, H460, PC-9, H23, H1299, C339, H3255, and H1975 were used as in vitro experiments. Western blot was used to observe expression of HIF-1α. MTT assay was used to investigate effects of different drug concentrations. The combination of EGFR-TKI (gefitinib) and HIF-1α inhibitors was used in EGFR wild-type, and EGFR- mutant cell lines. The combination index (CI) was used to determine the effect of drug combination. The mean CI (mCI) values more than 1.05 or less than 0.95 were defined as antagonism or synergism, respectively.
Result:
Western blot showed that HIF-1α expression was relatively high in EGFR- mutant cell lines and relatively low in EGFR wild-type cell lines. Under normoxia, HIF-1α expression increased in Hcc827 and H460 cell lines. Under hypoxia, HIF-1α expression increased in Hcc827R and H1975 cell lines. MTT assay showed that gefitinib was found to be superior to HIF-1α inhibitors in cytotoxicity effect on EGFR-TKI-sensitive NSCLC lines (PC9, Hcc827, C339, H3255). HIF-1α inhibitor was relatively better than gefitinib in cytotoxicity effect on EGFR-TKI-insensitive NSCLC cell lines (A549, H23, H460, H1299, Hcc827R, H1975). Under normoxia or hypoxia, cytotoxicity effect of HIF-1α inhibitor on EGFR-TKI-insensitive NSCLC cell lines (Hcc827R, H1975, A549, H460) was relatively better than gefitinib. Of five cell lines, including A549, Hcc827, Hcc827R, H460 and PC-9, their CI values for Gefitinib/HIF-1α inhibitor were 1.00, 0.925, 1.32, 0.76 and 1.23, respectively under normoxia. Data showed that cytotoxicity effect of HIF-1α inhibitor antagonized with gefitinib in Hcc827R and PC-9 cell lines. However, cytotoxicity effect of HIF-1α inhibitor synergized with gefitinib in the Hcc827, and H460 cell line. Of four cell lines, including A549, Hcc827, Hcc827R, and H460, their CI values for Gefitinib/HIF-1α inhibitor were 1.23, 1.17, 1.02, and 1.08, respectively under hypoxia. In this study, increased expression of HIF-1α in Hcc827 and H460 under normoxia may be related to synergistic cytotoxicity effect of HIF-1α inhibitors and gefitinib.
Conclusion:
HIF-1α inhibitors demonstrated anti-NSCLC activity in vitro and a selectively synergistic effect with gefitinib in EGFR-TKI-insensitive NSCLC cell line (H460). Our study suggested a potential treatment approach using HIF-1α inhibitors plus gefitinib.
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P3.07 - Immunology and Immunotherapy (ID 723)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.07-011 - Investigation of Autologous Tumor-Killing Effect of Effusion-Associated Lymphocytes in Malignant Pleural Effusion of Lung Cancer (ID 9513)
09:30 - 09:30 | Author(s): H. Yang
- Abstract
Background:
Many lung cancer patients developed malignant pleural effusion during the course of the disease. Previous studies revealed that the effusion associated lymphocytes (EAL) were in dysfunctional state which appeared to be immunosuppressed and unable to kill tumor cells. This study will evaluate the combined effects of IL-2, IL-12, αCD3 antibody (ab), and PD-1 ab on antitumor activity of lymphocytes. The underlying mechanism and relevant immune biomarkers will also be investigated.
Method:
We choose the malignant pleural effusion from lung cancer patients to analyze the association among lymphocytes, cancer cells, and cytokines in order to realize the lymphocyte immunity in the malignant pleural effusion of lung cancer patients. Flow cytometry was used to determined lymphocyte subpopulation. The Proliferation assay was performed to evaluate the effect of medication on lymphocytes. ELISA was used to evaluate cytokine level. Cell-mediated cytotoxicity assay was performed to evaluate the tumor-killing effect of EAL.
Result:
EAL were isolated from 21 malignant pleural effusions. Lymphocyte subpopulation was determied by flow cytometry, and total lymphocytes were composed of 8.9% exhausted T cells (CD3+/CD8+/ PD-1+), and 27.8% PD1+ NK cells. IL-2+αCD3 ab+pembrolizumab has demonstrated the trend toward to enhance the proliferation of EAL. IL-2+αCD3 ab or IL-2+IL-12+αCD3 ab or IL-2+IL-12+αCD3 ab+pembrolizumab demonstrated the trend for EAL to produce more IFN-γ. IL-2+αCD3 ab or IL-2+IL-12+αCD3 ab demonstred the trend for EAL to produce more IL-10. IL-2+αCD3+pembrolizumab did not demonstrated the trend for EAL to produce more IL-10. The addition of IL-2+αCD3 ab or IL-2+pembrolizumab showed the trend toward increased EAL cytolytic activity against autologous tumors (effector:target cells= 30:1). The addition of IL-2+αCD3 ab did not show the trend toward increased EAL cytolytic activity against autologous tumors in different conditions (effector:target cells= 10:1). The addition of IL-2+αCD3 ab or IL-12+αCD3 ab or IL-2+IL-12+αCD3 ab showed the trend toward increased EAL cytolytic activity against autologous tumors (effector:target cells= 3:1).
Conclusion:
The depressed cellular function of EAL may be potentially reversed with multiple signal stimulation, including IL-2 plus αCD3 ab, IL-2 plus pembrolizumab, IL-12 plus αCD3 ab or IL-2 plus IL-12 and αCD3 ab. Further studies are warranted in order to confirm the synergistic cytotoxicity effect of cytokines plus PD-1 inhibitors.
