The Role Of CEACAM1 In Regulating NK Cell Function

NK cell plays an effect through a variety of activating receptors and inhibitory receptors on their surface. At present, there are several known NK cell activation receptors, including NKG2D, NCRs family (NKp30, NKp44, NKp40) and so on. The inhibitory receptors mainly include KIRs, LAG-3 and TIGIT. In recent years, we found that carcinoembryonic antigen-related adhesion molecule 1 (CEACAM1) has the function of immunosuppressive molecule and has become a hotspot. CEACAM1 is an important member of the CEA family, which is widely expressed in tumor cells,endothelial cells, granulocytes, lymphocytes and epithelial cells. CEACAM1 is found mostly as a cis-homodimer. CEACAM1 and TIM-3 can form heterodimers.CEACAM1 can also interacts with NKG2D to suppress downstream signals.Previous studies have focused on the regulation of CEACAM1 on the metabolism and growth of tumor cells. In recent years, the research focus has shifted to its regulation of immune cell function. Co-blockade of CEACAM1 and TIM-3 on the T cell leads to enhancement of anti-tumor immune responses with improved elimination of tumor in mouse colorectal cancer models. Of which the efficacy was better than that of PD-1 antibody. The survival time of mice was prolonged and the tumor size was controlled.CEACAM1 is highly expressed on NK cells. We think of whether CEACAM1 can also significantly regulate the function of NK cells? So we do the research for that.First, we used RT-PCR and qPCR to compare the expression of CEACAM1 on various cell lines, and then use FACS to detect the expression of CEACAM1 on tumor cell lines and NK cell lines. In order to investigate the role of cytokines in the expression of CEACAM1 in NK cells, we selected IL-12 and IL-4 to treat NK cells.In order to study the effect of CEACAM1 interaction on NK cell function, we used lentivirus packaging system to overexpress CEACAM1 at 293T cell and co-culture with NK cell lines expressing CEACAM1 in different degrees to detect degrading levels and cytokine secretion. The results showed that NK-92 cell highly expressed CEACAM1,NKG cell lowly expressed CEACAM1 and CEACAM1 was not expressed or lowly expressed on tumor cells. IL-12 could significantly up-regulate the expression of CEACAM1 on NKG cells, and IL-4 had no obvious effect on NK-92 cell. overexpression of CEACAM1 on the 293T cells could reduce the degranulation levels of NK-92 and NKG cells during co-culture system, inhibit the secretion of Granzyme B of NKG cell, decrease the level of IFN-y secretion of NK-92 cell.CEACAM1 significantly inhibited direct killing and indirect regulation of NK cells,which also indicates that CEACAM1 may be a new target for immunotherapy by blocking CEACAM1 to reverse the exhausted of NK cells, and it may be used for anti-tumor treatment.