title: The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses.
abstract: The complement peptide C3a is a key component of the innate immune system and a major fragment produced following complement activation. We used a murine model of melanoma (B16-F0) to identify a hitherto unknown role for C3a-C3aR signaling in promoting tumor growth. The results show that the development and growth of B16-F0 melanomas is retarded in mice lacking C3aR, whereas growth of established melanomas can be arrested by C3aR antagonism. Flow cytometric analysis showed alterations in tumor-infiltrating leukocytes in the absence of C3aR. Specifically, neutrophils and CD4(+) T lymphocyte subpopulations were increased, whereas macrophages were reduced. The central role of neutrophils was confirmed by depletion experiments that reversed the tumor inhibitory effects observed in C3aR-deficient mice and returned tumor-infiltrating CD4(+) T cells to control levels. Analysis of the tumor microenvironment showed upregulation of inflammatory genes that may contribute to the enhanced antitumor response observed in C3aR-deficient mice. C3aR deficiency/inhibition was also protective in murine models of BRAF(V600E) mutant melanoma and colon and breast cancer, suggesting a tumor-promoting role for C3aR signaling in a range of tumor types. We propose that C3aR activation alters the tumor inflammatory milieu, thereby promoting tumor growth. Therapeutic inhibition of C3aR may therefore be an effective means to trigger an antitumor response in melanoma and other cancers.
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Jamileh A
authors.identifier: 0000-0002-0271-8396
authors.initials: JA
authors.lastname: Nabizadeh
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Helga D
authors.identifier: 0000-0002-3754-8788
authors.initials: HD
authors.lastname: Manthey
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Queensland 4029, Australia; and.
authors.forename: Frederik J
authors.identifier: 0000-0002-4782-3608
authors.initials: FJ
authors.lastname: Steyn
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Weiyu
authors.identifier: 0000-0003-4436-2743
authors.initials: W
authors.lastname: Chen
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Alexander
authors.identifier: 0000-0003-3584-7722
authors.initials: A
authors.lastname: Widiapradja
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Fazrena N
authors.initials: FN
authors.lastname: Md Akhir
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia; b.rolfe@uq.edu.au t.woodruff@uq.edu.au.
authors.forename: Trent M
authors.identifier: 0000-0003-1382-911X
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia; b.rolfe@uq.edu.au t.woodruff@uq.edu.au.
authors.forename: Barbara E
authors.identifier: 0000-0002-0468-1371
authors.initials: BE
authors.lastname: Rolfe
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D063646:Carcinogenesis / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D011951:Receptors, Complement / Q000172:deficiency / Q000276:immunology*
chemical_list: D011951:Receptors, Complement; C085567:complement C3a receptor