Complement-Dependent Modulation of Antitumor Immunity following Radiation Therapy

• A tumor-targeted complement inhibitor clears tumors after radiation therapy
• Complement inhibition increases apoptotic tumor cells after RT and is inflammatory
• Effect of complement inhibition on outcome of RT is neutrophil dependent
• Complement inhibition with RT modulates antitumor adaptive immune response

SummaryComplement is traditionally thought of as a proinflammatory effector mechanism of antitumor immunity. However, complement is also important for effective clearance of apoptotic cells, which can be an anti-inflammatory and tolerogenic process. We show that localized fractionated radiation therapy (RT) of subcutaneous murine lymphoma results in tumor cell apoptosis and local complement activation. Cotreatment of mice with tumor-targeted complement inhibition markedly improved therapeutic outcome of RT, an effect linked to early increases in apoptotic cell numbers and increased inflammation. Improved outcome was dependent on an early neutrophil influx and was characterized by increased numbers of mature dendritic cells and the subsequent modulation of T cell immunity. Appropriate complement inhibition may be a promising strategy to enhance a mainstay of treatment for cancer.

Graphical AbstractFigure optionsDownload as PowerPoint slide