Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis
Sergio Ortiz-Espinosa 1 , Xabier Morales 2 , Yaiza Senent 1 , Diego Alignani 3 , Beatriz Tavira 4 , Irati Macaya 5 , Borja Ruiz 5 , Haritz Moreno 5 , Ana Remírez 6 , Cristina Sainz 6 , Alejandro Rodriguez-Pena 2 , Alvaro Oyarbide 2 , Mikel Ariz 2 , Maria P Andueza 7 , Karmele Valencia 8 , Alvaro Teijeira 9 , Kai Hoehlig 10 , Axel Vater 10 , Barbara Rolfe 11 , Trent M Woodruff 11 , Jose Maria Lopez-Picazo 12 , Silvestre Vicent 13 , Grazyna Kochan 14 , David Escors 14 , Ignacio Gil-Bazo 15 , Jose Luis Perez-Gracia 16 , Luis M Montuenga 13 , John D Lambris 17 , Carlos Ortiz de Solorzano 18 , Fernando Lecanda 6 , Daniel Ajona 19 , Ruben Pio 8
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.