Modulation of the antitumor immune response by complement

Nat Immunol. 2008 Nov;9(11):1225-35. doi: 10.1038/ni.1655. Epub 2008 Sep 28.

Abstract

The involvement of complement-activation products in promoting tumor growth has not yet been recognized. Here we show that the generation of complement C5a in a tumor microenvironment enhanced tumor growth by suppressing the antitumor CD8(+) T cell-mediated response. This suppression was associated with the recruitment of myeloid-derived suppressor cells into tumors and augmentation of their T cell-directed suppressive abilities. Amplification of the suppressive capacity of myeloid-derived suppressor cells by C5a occurred through regulation of the production of reactive oxygen and nitrogen species. Pharmacological blockade of the C5a receptor considerably impaired tumor growth to a degree similar to the effect produced by the anticancer drug paclitaxel. Thus, our study demonstrates a therapeutic function for complement inhibition in the treatment of cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Complement Activation
  • Complement C3-C5 Convertases / genetics
  • Complement C5a / antagonists & inhibitors
  • Complement C5a / immunology*
  • Complement C5a / pharmacology
  • Down-Regulation
  • Female
  • Immunosuppression*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • Reactive Nitrogen Species / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor, Anaphylatoxin C5a / antagonists & inhibitors*
  • Receptor, Anaphylatoxin C5a / immunology
  • Receptor, Anaphylatoxin C5a / metabolism
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Reactive Nitrogen Species
  • Reactive Oxygen Species
  • Receptor, Anaphylatoxin C5a
  • Complement C5a
  • Complement C3-C5 Convertases