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 Therapy*
-
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