Triggering Receptor Expressed On Myeloid Cells-2(TREM-2) As Negative Immune Regulator Promote Lung Cancer Progress

Recently, with advances in the research of the immune suppressive cells, negative regulatory molecules and mechanisms of negative regulation, the immunotherapy strategies of negative regulation in lung cancer has attracted lots of attention. Triggering receptor expressed on myeloid cells-2(TREM-2) down-regulates phagocytosis function of dendritic cells (DC), macrophages and antigen presenting cells, reduces the release of inflammatory cytokines and therefore, alleviates inflammatory reactions by inhibitory signaling through the adapter protein DAP12, suggesting that TREM-2may be a negative regulatory molecule involved in regulation of immune response.To explore whether the tumor microenvironment could induce DC and antigen presenting cells to express TREM-2, and the roles of TREM-2mediated immune suppression in the immune tolerance of lung cancer, we detected the expression of TREM-2on peripheral blood mononuclear cells of lung cancer patients by flow cytometry and studied the expression and function of TREM-2on lung cancer mice model and lung cancer cell lines. We found that:1. Compared with healthy controls, TREM-2expressing mononuclear cell proportion, in lung cancer patients, increased obviously and TREM-2expression in mononuclear cells also augmented.2. Adding the culture supernatant of3LL lung cancer cell line (simulation of tumor microenvironment) to DC primary culture system promoted both the expression of TREM-2on DC surface and the percent of TREM-2+CD11c+DC; DC (both TREM-2+and TREM-2-) cultured in previous tumor simulation microenvironment positively sorted by magnetic bead inhibited T cell activation and proliferation, but if DC was firstly negative sorted by TREM-2-magnetic beads, and further selected by CD11c+positive sorting magnetic beads, these DC showed weaken inhibition of T cell activation of proliferation.3. TREM-2+CD11c+DC sorted by Flowcyte inhibited damage effects of NK cells to Yac-1cells and this inhibitory effect was blocked by anti-TREM-2monoclonal antibodies.4. In in situ3LL cell line induced lung cancer mice model, quantity of TREM-2+CD11c+DC in lung tissue increased dramatically, and expression of the surface MHC-II molecules la and CD86of DC dropped, furthermore, in vitro six hours’ stimulation of LPS and CPG reduced secretion of both IL-12and IFN-γ, but increased the secretion of IL-10.These suggest that TREM-2could promote lung cancer immune escape through the negative regulation of host immune function. This study about mechanisms of lung cancer immune escape provides theoretical foundation for new strategy of lung cancer immunotherapy.