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

Abstract

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.

• Authors: Sergio Ortiz-Espinosa, Xabier Morales, Yaiza Senent, Diego Alignani, Beatriz Tavira, Irati Macaya, Borja Ruiz, Haritz Moreno, Ana Remírez, Cristina Sainz, Alejandro Rodriguez-Pena, Alvaro Oyarbide, Mikel Ariz, Maria P Andueza, Karmele Valencia, Alvaro Teijeira, Kai Hoehlig, Axel Vater, Barbara Rolfe, Trent M Woodruff, Jose Maria Lopez-Picazo, Silvestre Vicent, Grazyna Kochan, David Escors, Ignacio Gil-Bazo, Jose Luis Perez-Gracia, Luis M Montuenga, John D Lambris, Carlos Ortiz de Solorzano, Fernando Lecanda, Daniel Ajona, Ruben Pio
• Journal: Cancer letters (Cancer Lett) Vol. 529 Pg. 70-84 (03 31 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34971753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• C5AR1 protein, human
• Receptor, Anaphylatoxin C5a
• Complement C5a

Topics

• Animals
• Cell Line, Tumor
• Complement C5a (immunology)
• Disease Models, Animal
• Extracellular Traps (immunology)
• Heterografts
• Humans
• Immunophenotyping
• Mice
• Models, Biological
• Myeloid-Derived Suppressor Cells (immunology, metabolism)
• Neoplasm Metastasis
• Neoplasms (etiology, metabolism, pathology)
• Neutrophils (immunology, metabolism)
• Receptor, Anaphylatoxin C5a (metabolism)