Transient Complement Inhibition Promotes a Tumor-Specific Immune Response through the Implication of Natural Killer Cells

Abstract

Although the role of the complement system in cancer development has been studied, its involvement in the development of an antitumoral immune response remains poorly understood. Using cobra venom factor (CVF) to inhibit the complement cascade via C3 molecule exhaustion in immunocompetent mice bearing B16gp33 melanoma tumors, we show that transient inhibition of the complement system allowed for the development of a more robust gp33-specific antitumoral CD8 þ T-cell response. This immune response proved to be natural killer (NK) dependent, suggesting an interaction of complement proteins with this cellular subset leading to T lymphocyte activation and enhanced cytotoxic T-cell activity against tumor cells. This study demonstrates for the first time the implication of the complement system in the development of NK-mediated cytotoxic T-cell-dependent antitumoral immune responses. The complement pathway could therefore be a potent therapeutic target to improve NK-dependent antitumoral immune responses in patients with cancer. Cancer Immunol Res; 2(3); 200-6. Ó2013 AACR.

Complement in cancer: untangling an intricate relationship

“…In some therapeutic anti-CD20 mAbs (for example, obinutuzumab) ADCC appears to be dominant over CDC when compared with rituximab or other antibodies. Preclinical and in vitro data indicate that complement activation, and in particular C3b deposition, inhibits rituximab-induced NK cell activation and ADCC 102–104 . Further, anti-CD20 mAbs have been implicated in the induction of ROS by monocytes with consequent inhibition of NK cell-mediated cytotoxicity 105 .…”

Innate immune mediators in cancer: between defense and resistance

“…The complement system also seems to influence NK cell‐mediated antitumor responses . Transient inhibition of complement allowed for the development of a more robust NK‐dependent antitumoral CD8 + T‐cell response against B16 melanoma cells grown in immunocompetent mice . More specifically, Gunn et al .…”

Tailoring Natural Killer cell immunotherapy to the tumour microenvironment

“…A therapeutic intervention designed to transiently deplete complement using cobra venom factor prior to tumour challenge increased the number of splenic and tumour-infiltrating NK cells and enhanced the anti-tumour cytotoxic T lymphocyte (CTL) response [60]. A model was proposed in which the expanded NK cell population leads to increased tumour cell lysis and antigen release facilitating DC maturation and antigen presentation and the enhanced generation of tumour-specific CD8 + T lymphocytes.…”