Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis

Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. In this study, we investigated the mechanisms by which complement C5a increases the capacity of polymorphonuclear MDSCs (PMN-MDSCs) to promote tumor growth and metastatic spread. Stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the formation of neutrophil extracellular traps (NETs). NETosis was dependent on the production of high mobility group box 1 (HMGB1) by cancer cells. Moreover, C5a induced the surface expression of the HMGB1 receptors TLR4 and RAGE in PMN-MDSCs. In a mouse lung metastasis model, inhibition of C5a, C5a receptor-1 (C5aR1) or NETosis reduced the number of circulating-tumor cells (CTCs) and the metastatic burden. In support of the translational relevance of these findings, C5a was able to stimulate migration and NETosis in PMN-MDSCs obtained from lung cancer patients. Furthermore, myeloperoxidase (MPO)-DNA complexes, as markers of NETosis, were elevated in lung cancer patients and significantly correlated with C5a levels. In conclusion, C5a induces the formation of NETs from PMN-MDSCs in the presence of cancer cells, which may facilitate cancer cell dissemination and metastasis.

Automated summary

This study reveals that C5a can enhance the capacity of PMN-MDSCs to promote tumor growth and metastasis by inducing the formation of NETs. The formation of NETs is dependent on the production of HMGB1 by cancer cells. Inhibiting C5a, C5aR1, or NETosis can reduce the number of circulating tumor cells and the metastatic burden in a mouse lung metastasis model. The translational relevance of these findings is supported by the stimulation of migration and NETosis in PMN-MDSCs obtained from lung cancer patients.