GDF-15Suppresses Maturation And Function Of Dendritic Cells

Cancer is still a serious threat to human health nowadays. While tumorimmunotherapy obtains more attention, tumor escape directly affects the effectiveness ofcancer immunotherapy. Defects in the tumor-bearing host’s own immune system is one ofthe main factors responsible for tumor escape. Tumor-derived factors (TDFs) induceddysfunction of immune cells plays an important role in tumor escape.Dendritic cells (DCs), known as the most powerful professional antigen-presentingcells (APCs), initiate an antigen-specific immune response by the recognition, acquisition,processing and presentation of antigens to na ve resting T cells. Defects in the DC systemare one of the main factors responsible for tumor immune escape. A variety of malignantcancers can recruit immature DCs (iDCs) to the tumor site and impede the cells’differentiation into functional APCs via the influence of TDFs that are enriched in thetumor microenvironment. Unlike mature DCs (mDCs), iDCs can induce immunedysfunction and immune tolerance by various mechanisms, partly facilitating tumorescape. To identify unknown TDFs that may suppress DC maturation and function, in ourprevious study, we established a high-throughput screening technology based on a humanliver tumor T7phage cDNA library and screened all of the proteins derived fromhepatoma cells that potentially interact with iDCs. Among the tumor-related proteins thatwe screened, growth/differentiation factor-15(GDF-15) was chosen for further study.GDF-15, also known as macrophage inhibitory cytokine-1, is a member of thetransforming growth factor-β (TGF-β) superfamily, which plays a key role in prenataldevelopmen and the regulation of both cellular responses to stress signals andinflammation and tissue repair after acute injuries in adulthood. The dysregulation ofGDF-15expression and signaling pathways has been associated with diverse humandiseases and cancer progression. However, little is known about the interaction betweenGDF-15and immune cells.Our study aims at investigating the effects of GDF-15on maturation and function ofDCs. Investigations focusing on the following aspects has been down:(1) cell morphous;(2) membrane molecules expressions;(3) phagocytosis;(4) secretion of pro-andanti-inflammatory cytokines;(5) T cells stimulatory capacity and CTL activation inducedby DCs;(6) the ability of DCs to stimulate anti-tumor specific immune response in vivo.Our study has demonstrated that GDF-15could inhibit surface protrusions formationduring DCs maturation, suppress CD83, CD86and HLA-DR expression, enhancephagocytosis, reduce IL-12and elevate TGF-β1secretion, inhibit T cells stimulatorycapacity and CTL activation, inhibit the ability of DCs to stimulate anti-tumor specificimmune response in vivo.These results first indicated that GDF-15could inhibit DCs maturation and function,promote tumor proliferation by inhibiting the ability of DCs to stimulate anti-tumorspecific immune response, indicating that GDF-15may act as one of the critical moleculesinvolved in tumor escape and may be a novel target in tumor immunotherapy. Our presentstudies laid a foundation for further revealing the possible mechanisms of how GDF-15affects DCs maturation and promote tumor escape.