Abstract 2400: Epithelial-mesenchymal transition in hepatocellular carcinoma leads to downregulation of adaptive immunity via COX-2 pathway

Abstract

Abstract The immune system targets pre-malignant and malignant cells and can attenuate or eliminate carcinogenesis. Epithelial-mesenchymal transition (EMT) is known to promote tumor progression in hepatocellular carcinoma (HCC). It is, however, unknown whether EMT promotes HCC by dysregulating the immune system. A clear understanding of the mechanisms underlying immune evasion in HCC may reveal targets that can be exploited for immunotherapy. In this study, we have used the murine HCC cell line 1MEA that we have successfully used to establish a syngeneic mouse model of aggressive HCC. The cells were exposed to TGFβ-1 (2ng/ml) and EGF (50ng/ml), two well-established inducers of EMT in HCC. Induction of EMT was confirmed by analysis of the gene expression profiles of E-cadherin, albumin, fibronectin and collagen I. Effects on clonogenicity were analyzed using colony formation assays. Effects on adaptive immunity were examined by analyzing gene and protein expression of major histocompatibility complexes I and II (MHC I and MHC II). The role of cyclooxygenase-2 (COX-2) was determined by examining the effect of the selective COX-2 inhibitor, celecoxib (1μM). Exposure to TGFβ-1 and EGF led to downregulation of E-cadherin and albumin and upregulation of fibronectin and collagen I. TGFβ-1 and EGF both promoted increased clonogenicity. Interestingly, exposure to TGFβ-1 and EGF both resulted in significant downregulation of both gene and protein expression of MHC I and MHC II. However, pre-treatment of cells with celecoxib significantly reversed these effects. Consequently, we conclude that EMT induction in HCC is associated with downregulation of adaptive immunity in a manner dependent on the COX-2 pathway. Immunotherapeutic targeting of COX-2 may, therefore, be a useful strategy for HCC management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2400. doi:1538-7445.AM2012-2400