Modulation of the antitumor immune response by complement.
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.
Markiewski
Maciej M
MM
Department of Pathology and Laboratory Medicine, Medical School of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
DeAngelis
Robert A
RA
Benencia
Fabian
F
Ricklin-Lichtsteiner
Salome K
SK
Koutoulaki
Anna
A
Gerard
Craig
C
Coukos
George
G
Lambris
John D
JD
D000818:Animals; D003167:Complement Activation; D050577:Complement C3-C5 Convertases / Q000235:genetics; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D050577:Complement C3-C5 Convertases