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Combined Yeast ß-Glucan and Antitumor Monoclonal Antibody Therapy Requires C5a-Mediated Neutrophil Chemotaxis via Regulation of Decay-Accelerating Factor CD55

¹ Tumor Immunobiology Program of the James Graham Brown Cancer Center, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky and ² Complement Biology Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom

Requests for reprints: Jun Yan, James Graham Brown Cancer Center, University of Louisville, Room 119A, 580 South Preston Street, Louisville, KY 40202. Phone: 502-852-3628; Fax: 502-852-2123; E-mail: jun.yan{at}louisville.edu.

Administration of a combination of yeast-derived ß-glucan with antitumor monoclonal antibodies (mAb) has significant therapeutic efficacy in a variety of syngeneic murine tumor models. We have now tested this strategy using human carcinomas implanted in immunocompromised severe combined immunodeficient mice. Combined immunotherapy was therapeutically effective in vivo against NCI-H23 human non–small-cell lung carcinomas, but this modality was surprisingly ineffective against SKOV-3 human ovarian carcinomas. Whereas NCI-H23 tumors responded to this combination therapy with increased intratumoral neutrophil infiltration and C5a production, these responses were lacking in treated SKOV-3 tumors. Further results suggested that SKOV-3 tumors were protected by up-regulation of the membrane complement regulatory protein CD55 (decay-accelerating factor). Blockade of CD55 in vitro led to enhanced deposition of C activation product C3b and increased cytotoxicity mediated by ß-glucan–primed neutrophils. In vivo, administration of anti-CD55 mAb along with ß-glucan and anti–Her-2/neu mAb caused tumor regression and greatly improved long-term survival in animals bearing the previously resistant SKOV-3 tumors. This was accompanied by increased intratumoral neutrophil accumulation and C5a production. We conclude that CD55 suppresses tumor killing by antitumor mAb plus ß-glucan therapy (and, perhaps, in other circumstances). These results suggest a critical role for CD55 to regulate iC3b and C5a release and in turn to influence the recruitment of ß-glucan–primed neutrophils eliciting killing activity. [Cancer Res 2007;67(15):7421–30]

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