Tumor Necrosis Factor-related Apoptosis Inducing Ligand Immune Function Study

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) efficiently induces apoptosis in numerous tumor cells but not in the majority of normal cells, suggesting that it could be a promising anticancer biotherapeutic. To date, five TRAIL receptors in human have been identified including TRAIL-R1(DR4), TRAIL-R2(DR5), TRAIL-R3(DcR1, TRID), TRAIL-R4(DcR2, TRUNDD) and OPG (osteoprotegerin). Among these receptors, DR4and DR5possess an intracellular tail containing death domain, which engages the apoptotic machinery upon TRAIL stimulation. DcR2has a truncated, cytoplasmic death domain, whereas DcRl has no death domain. OPG is a soluble TRAIL receptor. DcR1, DcR2and OPG could bind with TRAIL, but couldn’t transfer cell death signal, so that, they are termed as decoy receptors. In mice, only one death receptor (mDR5), which is homologous to human DR5, and two decoy receptors (mDcRl and mDcR2) have been found.Up to date, most researches on TRAIL have been focused on its ability to induce apoptosis in cancer cells. However, since TRAIL and its receptors are expressed on many normal cells, physiological roles of TRAIL are much less well understood. Mice with knockout of TRAIL and its receptors develop normally, but lead to tumor metastasis easily, suggesting that TRAIL/TRAIL receptors are involved in the regulation of tumor immunesurveillance. Moreover, TRAIL-1-mice were more susceptible to autoimmune arthritis and diabetes. TRAIL-R-1-mice infected with different pathogens display enhanced innate immune responses. These results suggest that TRAIL/TRAIL-R system is capable of modulating immune response.CD4+CD25+regulatory T cells (Tregs) account for5-10%of mature CD4+T cell population in mouse and human, while about1-2%of Treg can be measured in whole blood. Treg cells control key aspects of tolerance to self-Ags, rending them crucial in the prevention of autoimmune responses. The transcription factor Foxp3plays a key role in CD4+CD25+Treg development and function, and represents a specific marker for these cells. Treg in tumor microenvironment are usually elevated and likely activated during tumor progression to execute suppressor function. CD4+CD25+Treg cells are one mechanism of tumor evasion that provides targets for testing novel anticancer treatment strategies. Blocking of the TRAIL/DR5pathway results in a significant reduction of the suppressive activity as well as the cytotoxic effects of Treg in vitro and in vivo.In the present study, we used a TRAIL-resistant murine hepatocellular cell line of Hepa1-6to elucidate the physiological role, especially the immune regulatory function of TRAIL. We found that Hepal-6cells 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. Intratumoral injection of TRAIL decreased intratumoral CD4+CD25+Treg cells but didn’t affect Treg cells in draining lymph nodes and spleen. Mouse DR5(mDR5) expression could be detected on the surface of activated CD4+CD25+Treg in tumor tissue, but not on the naive CD4+CD25+Treg cells. Furthermore, TRAIL could induce apoptosis of tumor-activated CD4+CD25+Treg cells, but not of the CD4+CD25-T cells. Decrease of CD4+CD25+Treg thus augmented the tumor-specific CD8+CTL numbers and their cytotoxicity to the tumor cells.These data provide novel evidences at first time for the immune regulatory function of TRAIL, and may throw some light on TRAIL clinical application in tumor therapy.