title: TRAIL suppresses tumor growth in mice by inducing tumor-infiltrating CD4(+)CD25 (+) Treg apoptosis.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a promising and novel anticancer cytokine, specifically kills numerous tumor cells by apoptosis. However, some malignancies are resistant to TRAIL treatment in clinical trials, thus limiting its therapeutic potential. In the present study, the TRAIL-resistant murine hepatocellular carcinoma cell line Hepa1-6 was used to elucidate the physiological significance of TRAIL resistance, especially with respect to the immune regulatory function of TRAIL. Hepa1-6 cells were resistant to TRAIL-induced apoptosis in vitro; however, intratumoral injection of recombinant soluble TRAIL inhibited tumor growth and prolonged survival time in tumor-bearing mice. Local TRAIL treatment decreased the number of intratumoral CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) but did not affect CD4(+)CD25(+)Foxp3(+) Tregs in the draining lymph nodes and spleen. Further investigation showed that TRAIL induced apoptosis of tumor-activated CD4(+)CD25(+)Foxp3(+) Tregs, but not of CD4(+)CD25(-) T cells. Moreover, mouse TRAIL receptor DR5 expression was detected on the surface of the tumor-infiltrating CD4(+)CD25(+)Foxp3(+) Tregs, but not on naïve CD4(+)CD25(+)Foxp3(+) Tregs. Interestingly, intratumoral injection of TRAIL not only decreased the number of CD4(+)CD25(+)Foxp3(+) Tregs but also increased the number of tumor-specific CD8(+) CTL and augmented their cytotoxicity to the tumor cells. These data provide the novel evidence for an immune regulatory function of TRAIL and may shed light on the clinical application of TRAIL.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China.
authors.forename: Zhijuan
authors.initials: Z
authors.lastname: Diao
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.forename: Jieqing
authors.initials: J
authors.lastname: Zhu
authors.forename: Haiqin
authors.initials: H
authors.lastname: Yuan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ru
authors.forename: Shilian
authors.initials: S
authors.lastname: Liu
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Dexian
authors.initials: D
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000494:pharmacology*
chemical_list: C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D053221:TNF-Related Apoptosis-Inducing Ligand