Combined yeast {beta}-glucan and antitumor monoclonal antibody therapy requires C5a-mediated neutrophil chemotaxis via regulation of decay-accelerating factor CD55.
Administration of a combination of yeast-derived beta-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 beta-glucan-primed neutrophils. In vivo, administration of anti-CD55 mAb along with beta-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 beta-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 beta-glucan-primed neutrophils eliciting killing activity.
Tumor Immunobiology Program of the James Graham Brown Cancer Center, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Bing
B
Li
Daniel J
DJ
Allendorf
Richard
R
Hansen
Jose
J
Marroquin
Daniel E
DE
Cramer
Claire L
CL
Harris
Jun
J
Yan
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018958:CD55 Antigens / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D015926:Complement C3a / Q000502:physiology; D015936:Complement C5a / Q000502:physiology*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014407:Tumor Cells, Cultured; D047071:beta-Glucans / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D018958:CD55 Antigens; D047071:beta-Glucans; D015926:Complement C3a; D015936:Complement C5a