Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models.
Antitumor mAb bind to tumors and activate complement, coating tumors with iC3b. Intravenously administered yeast beta-1,3;1,6-glucan functions as an adjuvant for antitumor mAb by priming the inactivated C3b (iC3b) receptors (CR3; CD11b/CD18) of circulating granulocytes, enabling CR3 to trigger cytotoxicity of iC3b-coated tumors. Recent data indicated that barley beta-1,3;1,4-glucan given orally similarly potentiated the activity of antitumor mAb, leading to enhanced tumor regression and survival. This investigation showed that orally administered yeast beta-1,3;1,6-glucan functioned similarly to barley beta-1,3;1,4-glucan with antitumor mAb. With both oral beta-1,3-glucans, a requirement for iC3b on tumors and CR3 on granulocytes was confirmed by demonstrating therapeutic failures in mice deficient in C3 or CR3. Barley and yeast beta-1,3-glucan were labeled with fluorescein to track their oral uptake and processing in vivo. Orally administered beta-1,3-glucans were taken up by macrophages that transported them to spleen, lymph nodes, and bone marrow. Within the bone marrow, the macrophages degraded the large beta-1,3-glucans into smaller soluble beta-1,3-glucan fragments that were taken up by the CR3 of marginated granulocytes. These granulocytes with CR3-bound beta-1,3-glucan-fluorescein were shown to kill iC3b-opsonized tumor cells following their recruitment to a site of complement activation resembling a tumor coated with mAb.
Hong
Feng
F
Tumor Immunobiology Program of the James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Yan
Jun
J
Baran
Jarek T
JT
Allendorf
Daniel J
DJ
Hansen
Richard D
RD
Ostroff
Gary R
GR
Xing
Pei Xiang
PX
Cheung
Nai-Kong V
NK
Ross
Gordon D
GD
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000187:drug effects* / Q000276:immunology; D003176:Complement C3 / Q000187:drug effects; D005936:Glucans / Q000494:pharmacology*; D008221:Lymphoid Tissue / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D047071:beta-Glucans
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D003176:Complement C3; D005936:Glucans; D016177:Macrophage-1 Antigen; D047071:beta-Glucans; C033363:beta-1,3-glucan