Beta-glucan, a "specific" biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18).
beta-Glucans were identified 36 years ago as a biologic response modifier that stimulated tumor rejection. In vitro studies have shown that beta-glucans bind to a lectin domain within complement receptor type 3 (CR3; known also as Mac-1, CD11b/CD18, or alphaMbeta2-integrin, that functions as an adhesion molecule and a receptor for factor I-cleaved C3b, i.e., iC3b) resulting in the priming of this iC3b receptor for cytotoxicity of iC3b-opsonized target cells. This investigation explored mechanisms of tumor therapy with soluble beta-glucan in mice. Normal mouse sera were shown to contain low levels of Abs reactive with syngeneic or allogeneic tumor lines that activated complement, depositing C3 onto tumors. Implanted tumors became coated with IgM, IgG, and C3, and the absent C3 deposition on tumors in SCID mice was reconstituted with IgM or IgG isolated from normal sera. Therapy of mice with glucan- or mannan-rich soluble polysaccharides exhibiting high affinity for CR3 caused a 57-90% reduction in tumor weight. In young mice with lower levels of tumor-reactive Abs, the effectiveness of beta-glucan was enhanced by administration of a tumor-specific mAb, and in SCID mice, an absent response to beta-glucan was reconstituted with normal IgM or IgG. The requirement for C3 on tumors and CR3 on leukocytes was highlighted by therapy failures in C3- or CR3-deficient mice. Thus, the tumoricidal function of CR3-binding polysaccharides such as beta-glucan in vivo is defined by natural and elicited Abs that direct iC3b deposition onto neoplastic cells, making them targets for circulating leukocytes bearing polysaccharide-primed CR3. Therapy fails when tumors lack iC3b, but can be restored by tumor-specific Abs that deposit iC3b onto the tumors.
Yan
J
J
Division of Experimental Immunology, Department of Pathology, University of Louisville, KY 40292, USA.
Vetvicka
V
V
Xia
Y
Y
Coxon
A
A
Carroll
M C
MC
Mayadas
T N
TN
Ross
G D
GD
D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology; D018821:CD18 Antigens / Q000276:immunology*; D003176:Complement C3 / Q000378:metabolism; D003179:Complement C3b / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D005936:Glucans / Q000008:administration & dosage / Q000627:therapeutic use*; D007106:Immune Sera / Q000378:metabolism; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007155:Immunologic Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D016177:Macrophage-1 Antigen / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D014407:Tumor Cells, Cultured; D015054:Zymosan / Q000008:administration & dosage / Q000627:therapeutic use
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D018821:CD18 Antigens; D003176:Complement C3; D005936:Glucans; D007106:Immune Sera; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007155:Immunologic Factors; D016177:Macrophage-1 Antigen; D003179:Complement C3b; D015054:Zymosan