TRAIL in the regulation of tumor invasion CD4 ~ CD25 ~ Treg
|School||Beijing Union Medical College|
|Course||Biochemistry and Molecular Biology|
|Keywords||tumor necrosis factor-related apoptosis-inducing ligand CCL22 CD4~+CD25~+ T regulatory cell|
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is also designated as Apo-2 ligand, is a typical member of the structurally related TNF family. TRAIL efficiently induces apoptosis in numerous tumor cells, but not in the majority of normal cells, so that TRAIL is regarded as a promising anticancer agent due to its tumor specific toxicity. To date, five TRAIL receptors in human have been identified including TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcRl, TRID), TRAIL-R4 (DcR2, TRUNDD) and OPG (osteoprotegerin). Among these receptors, DR4 and DR5 could transmit an apoptotic signal upon TRAIL stimulation. In mouse, only one death receptor (mDR5), which is homologous to human DR5, and two decoy receptors (mDcRl and mDcR2) have been found.TRAIL has been widely studied for its apoptosis mechanism and anti-tumor function. However, up to date, the physiological roles of TRAIL are still not very clear. In previous studies, TRAIL was reported to be involved in the regulation of tumor immune surveillance. Knockout of TRAIL or TRAIL receptor led to tumor metastasis, and TRAIL was considered to play a role in autoimmune diseases, like experimental autoimmune encephalomyelitis (EAE), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). TRAIL was also reported to regulate immunological cell proliferation, maturation and migration.Regulatory T cell (Treg), originally termed as suppressor T cell, is thought to control key aspects of immunological tolerance to self-antigen. Treg has become one hot spot of immunity academe. So far, some progress about the relation of Treg and tumor, autoimmune diseases, transplantation rejection and other human diseases have been made and Treg thus might be a potential target for these diseases.In the previous study, Hepal-6, a TRAIL-resistant murine hepatocellular cell line was used to elucidate the immune regulatory function of TRAIL. We found that Hepa1-6 cells were resistant to TRAIL-induced apoptosis in vitro, but intratumoral injection of TRAIL in tumor-bearing mice could inhibit tumor growth and prolong survival period. A series of studies provided evidences that TRAIL could induce apoptosis of tumor-infiltrating CD4+CD25+Treg cells, augment the tumor-specific CD8+CTL numbers and immune activity.In the present study, function of TRAIL on tumor-infiltrating CD4+CD25+Treg cells will be elucidated in different tumor models. We depleted tumor-infiltrating CD4+CD25+Treg in Hepal-6 tumor with anti-CD25 antibody. Hepal-6 tumor growth was significantly suppressed in CD25 depletion group and TRAIL plus treatment did not further decrease the Hepal-6 tumor size. This result further confirmed that TRAIL induced tumor-infiltrating CD4+CD25+Treg apoptosis played important role in preventing Hepal-6 tumor growth.To determine whether function of TRAIL on tumor-infiltrating CD4+CD25+Treg is tumor-specific or universal,4T1 mammry tumor model was analysised. We found that 4T1 cells were moderate resistant to TRAIL in vitro, but TRAIL treatment didn’t inhibit 4T1 tumor growth in vivo. To our surprise, tumor infiltrating CD4+CD25+Treg cells were increased significantly in TRAIL treatment group. Further study showed that TRAIL treatment increased CCL22 secretion from 4T1 cells. These data indicated augmention in CCL22 secretion of 4T1 cancer cells might recruit more Tregs after TRAIL administration, therefore, leading to increased tumor infiltrating CD4+CD25+Treg. However, TRAIL did not enhance CCL22 secretion from Hepal-6 tumor cells. TRAIL could induce tumor-infiltrating CD4+CD25+Treg apoptosis in Hepa1-6 tumor model, but in 4T1 tumor model, TRAIL increased CCL22 secretion, and thus recruited more CD4+CD25+Treg into tumor, while didn’t induce 4T1 tumor cell apoptosis. This study suggested that the sensibility of tumor to TRAIL treatment is not only related to tumor cell itself, but also related to distinct machinsms of TRAIL on tumor infiltrating CD4+CD25+Treg. This study provides novel data for the physiological function of TRAIL and cancer therapy application.