PUB015 A Pooled Analysis of Efficacy and Safety of CTLA-4 Antigen in the Treatment of Cancer

Abstract

suppresses differentiation-associated genes, thereby maintaining selfrenewal and the pluripotency of the cells. Oct4 can regulate the transcription of the glycolytic enzymes Hk2 and Pkm2, which determine the rate of glycolytic flux in embryonic stem cells. This study aimed to investigate whether Collagen XVII can activate the pluripotent gene expression and subsequently alter the metabolic state of lung CSCs, thus enhancing tumor invasion, chemoresistance and initiation in lung CSC. Method: Several single cell clones of A549 lung cancer cells with overexpression of Collagen XVII were set up to examine the link and possible mechanism among Collagen XVII and pluripotent gene expressions in lung CSCs and investigate if dysregulation of Collagen XVII can cause metabolic reprogramming through activation of Oct4. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) are measured using the Seahorse XF24 extracellular flux analyzer. CRISPR/Cas9 system was used for knock-out of Collagen XVII expression in lung cancer cells. Result: We demonstrated that overexpression of Collagen XVII in lung cancer cells increased cancer stemness including migration, invasion, chemoresistance, decreased DNA damage, increased EMT markers and enhanced tumor formation in vivo. Oct4 expression was activated in lung cancer cells with overexpression of Collagen XVII through AKT/GSK-3b/b-catenin pathway. Overexpression of Collagen XVII also increased glycolytic capacity and the lactate level, compared to parental A549 lung cancer cells. The expression of Oct4 was downregulated by knock-out of Collagen XVII, thus resulting in decreased extracellular acidification rate and oxygen consumption rate in lung cancer cells. Conclusion: We found for the first time that Collagen XVII can activate Oct4 through upregulation of AKT/GSK-3b/b-catenin pathway, and thus alter metabolic reprogramming including glycolysis and oxygenation consumption in lung cancer cells. Further investigation to elucidate which metabolism associated proteins is responsible for the stemness of lung cancer stem cells is mandatory.Background: Anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), including ipilimumab and tremelimumab, showed significantly improve survival in patients with melanoma. However, treatment of CTLA-4 antigen in patients with other cancers, especially lung cancer, showed inconsistent survival benefit. We conducted this meta-analysis to explore the efficacy and safety of CTLA-4 antigen compared to the conventional regimens or other immunotherapy during cancer treatment by reviewing randomized trials. Method: Until January 2017, an electronic systematic literature search was performed up in Pubmed and Cochrone Library. ASCO and ESMO were reviewed seriously as well. Median overall survival (mOS), median progression-free survival (mPFS), hazard ratio (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. Result: We found that mOS and mPFS were significantly improved in all cancers (HR¼0.83, 95%, CI¼0.76-0.90; HR¼0.7...