Complement-Dependent Modulation of Antitumor Immunity following Radiation Therapy

• Published in: Cell reports (Cambridge) 2014-08, Vol.8 (3), p.818-830
• Main Authors: Elvington, Michelle, Scheiber, Melissa, Yang, Xiaofeng, Lyons, Katherine, Jacqmin, Dustin, Wadsworth, Casey, Marshall, David, Vanek, Kenneth, Tomlinson, Stephen
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Line, Tumor; Complement Activation; Complement C3d - antagonists & inhibitors; Complement Inactivating Agents - pharmacology; Complement Inactivating Agents - therapeutic use; Dendritic Cells - immunology; Immunomodulation; Lymphoma - immunology; Lymphoma - radiotherapy; Lymphoma - therapy; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Subcutaneous Tissue - pathology; T-Lymphocytes - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.06.051

Complement 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. [Display omitted] •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 Radiation therapy (RT) is a mainstay treatment for many cancers, and an emerging paradigm is that antitumor effects of RT depend to varying extents on the immune system. Here, Elvington et al. demonstrate that complement inhibition, which is normally anti-inflammatory, promotes inflammation within locally irradiated tumors. Early inflammation and neutrophil influx is linked to a subsequent increase in numbers of mature dendritic cells and the modulation of T cell immunity with a marked improvement in the therapeutic outcome of RT.