ИСТИНА

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells that under normal conditions may differentiate into mature macrophages, granulocytes and dendritic cells. Under the influence of inflammatory cytokines, these cells become MDSC, acquire immunosuppressive phenotype and enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for induction, expansion and suppressive activity of MDSC. In this study we evaluated the effects of systemic TNF ablation by Etanercept and Infliximab on tumor-induced expansion of MDSC in vivo using TNF humanized (hTNF KI) mice. Mice undergoing systemic TNF ablation were transplanted with MCA 205 tumor cells. Tumor growth and MDSC accumulation in the blood was monitored during the next three weeks. To study the impact of systemic TNF inhibition on the functional properties of MDSC, we examined ROS and NO production in vivo in blood MDSC of tumor-bearing hTNF KI mice and ex vivo in T-cell proliferation assay. We found that both Etanercept and Infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma and significantly reduced accumulation of MDSC in the blood. Furthermore, we observed that systemic TNF inhibitors not only reduced MDSC numbers but also affected their suppressive function. We detected a significant reduction in NO in blood MDSC in both Etanercept- and Infliximab-treated mice, whereas significant difference in ROS production was only detected in Etanercept-treated tumor-bearing mice. MDSC isolated from tumor-bearing mice under Infliximab or Etanercept treatment were not able to prevent T-cell proliferation indicating that their suppressive function was compromised. In several experiments we observed that mice undergoing TNF ablation not only have delayed tumor growth but also have fewer metastasis. Thus, we found that TNF neutralization reduces tumor development, MDSC accumulation and affects suppressive function of MDSC. Our study provides example of pro-tumorigenic activity of endogenous TNF that involves MDSC and may be useful for future validation of cell-type-specific anti-cytokine therapy targeting TNF on myeloid cells.