title: Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression.
abstract: The complement system contributes to various immune and inflammatory diseases, including cancer. In this study, we investigated the capacity of lung cancer cells to activate complement and characterized the consequences of complement activation on tumor progression. We focused our study on the production and role of the anaphylatoxin C5a, a potent immune mediator generated after complement activation. We first measured the capacity of lung cancer cell lines to deposit C5 and release C5a. C5 deposition, after incubation with normal human serum, was higher in lung cancer cell lines than in nonmalignant bronchial epithelial cells. Notably, lung malignant cells produced complement C5a even in the absence of serum. We also found a significant increase of C5a in plasma from patients with non-small cell lung cancer, suggesting that the local production of C5a is followed by its systemic diffusion. The contribution of C5a to lung cancer growth in vivo was evaluated in the Lewis lung cancer model. Syngeneic tumors of 3LL cells grew slower in mice treated with an antagonist of the C5a receptor. C5a did not modify 3LL cell proliferation in vitro but induced endothelial cell chemotaxis and blood-vessels formation. C5a also contributed to the immunosuppressive microenvironment required for tumor growth. In particular, blockade of C5a receptor significantly reduced myeloid-derived suppressor cells and immunomodulators ARG1, CTLA-4, IL-6, IL-10, LAG3, and PDL1 (B7H1). In conclusion, lung cancer cells have the capacity to generate C5a, a molecule that creates a favorable tumor microenvironment for lung cancer progression.
authors.affiliation: Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Corrales
authors.forename: Daniel
authors.initials: D
authors.lastname: Ajona
authors.forename: Stavros
authors.initials: S
authors.lastname: Rafail
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lasarte
authors.forename: Jose I
authors.initials: JI
authors.lastname: Riezu-Boj
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pajares
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000276:immunology / Q000473:pathology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000276:immunology / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000276:immunology / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D015936:Complement C5a / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology / Q000628:therapy; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a