Growth differentiation factor-15 suppresses maturation and function of dendritic cells and inhibits tumor-specific immune response.
Dendritic cells (DCs) play a key role in the initiation stage of an antigen-specific immune response. A variety of tumor-derived factors (TDFs) can suppress DC maturation and function, resulting in defects in the tumor-specific immune response. To identify unknown TDFs that may suppress DCs maturation and function, we established a high-throughput screening technology based on a human liver tumor T7 phage cDNA library and screened all of the proteins derived from hepatoma cells that potentially interact with immature DCs. Growth/differentiation factor-15 (GDF-15) was detected and chosen for further study. By incubation of DCs cultures with GDF-15, we demonstrate that GDF-15 can inhibit surface protrusion formation during DC maturation; suppress the membrane expression of CD83, CD86 and HLA-DR on DCs; enhance phagocytosis by DCs; reduce IL-12 and elevate TGF-β1 secretion by DCs; inhibit T cell stimulation and cytotoxic T lymphocyte (CTL) activation by DCs. By building tumor-bearing mouse models, we demonstrate that GDF-15 can inhibit the ability of DCs to stimulate a tumor-specific immune response in vivo. These results indicate that GDF-15 may be one of the critical molecules that inhibit DC maturation and function and are involved in tumor immune escape. Thus, GDF-15 may be a novel target in tumor immunotherapy.
The State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China ; Department of Biopharmaceutics, Fourth Military Medical University, Xi'an, Shaanxi, China.
Zhizhong
Z
Zhou
Weina
W
Li
Yang
Y
Song
Lili
L
Wang
Kuo
K
Zhang
Jing
J
Yang
Wei
W
Zhang
Haichuan
H
Su
Yingqi
Y
Zhang
D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D055436:Growth Differentiation Factor 15 / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010587:Phagocytosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D019139:Tumor Escape
C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor