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: Jamileh A Nabizadeh, Helga D Manthey, Frederik J Steyn, Weiyu Chen, Alexander Widiapradja, Fazrena N Md Akhir, Glen M Boyle, Stephen M Taylor, Trent M Woodruff, Barbara E Rolfe
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 196 Issue 11 Pg. 4783-92 (06 01 2016) ISSN: 1550-6606 [Electronic] United States
• PMID: 27183625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by The American Association of Immunologists, Inc.

Chemical References

• Receptors, Complement
• complement C3a receptor

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, pathology)
• Carcinogenesis (immunology)
• Cells, Cultured
• Female
• Melanoma (genetics, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Neutrophils (immunology, pathology)
• Receptors, Complement (deficiency, immunology)