Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-06, Vol.76 (11), p.3179-3188
• Main Authors: Lin, Dandan, Lei, Lei, Liu, Yonghao, Zhang, Yinsheng, Hu, Bo, Bao, Guangming, Song, Yuan, Jin, Ziqi, Liu, Chunliang, Mei, Yu, Sandikin, Dedy, Wu, Yan, Zhao, Lixiang, Yu, Xiao, Liu, Haiyan
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Membrane - metabolism; Cell Proliferation; Cytotoxicity, Immunologic - immunology; Immunoenzyme Techniques; Interleukin-1alpha - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Liver Neoplasms, Experimental - immunology; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Tumor Cells, Cultured
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-2658

Hepatocellular carcinoma is a worldwide health problem with limited treatment options and poor prognosis. Inflammation associated with liver injury and hepatocyte regeneration can lead to fibrosis, cirrhosis, and eventually, hepatocellular carcinoma. IL1α is one of the most important inflammatory cytokines involved in inflammation and tumor development. IL1α presents as multiple forms in vivo, including precursor, propiece, membrane, and secreted forms, and their functions have been thought to be different. The role of membrane IL1α in hepatocellular carcinoma tumorigenesis is still not clear. Here, we examined the functions of membrane IL1α in murine hepatocellular carcinoma models. We found that membrane IL1α potently inhibited hepatocellular carcinoma tumor growth. Further studies showed that membrane IL1α promoted T- and natural killer (NK)-cell activation in vivo IFNγ production by CD8(+) T and NK cells was also increased as a result of membrane IL1α expression. Moreover, the cytotoxicity of the CTL and NK cells was also enhanced by membrane IL1α expression. Furthermore, in vitro studies demonstrated that membrane IL1α could directly activate T cells and NK cells in a cell contact-dependent manner. Conversely, depletion of both CD8(+) T and NK cells suppressed the antitumor activity of membrane IL1α. Our studies demonstrated that membrane IL1α could promote antitumor immune responses through activation of T and NK cells. Thus, our findings provide new insights of IL1α functions during hepatocellular carcinoma development. Cancer Res; 76(11); 3179-88. ©2016 AACR.