Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway.
Anti-tumor mAbs hold promise for cancer therapy, but are relatively inefficient. Therefore, there is a need for agents that might amplify the effectiveness of these mAbs. One such agent is beta-glucan, a polysaccharide produced by fungi, yeast, and grains, but not mammalian cells. Beta-glucans are bound by C receptor 3 (CR3) and, in concert with target-associated complement fragment iC3b, elicit phagocytosis and killing of yeast. Beta-glucans may also promote killing of iC3b-opsonized tumor cells engendered by administration of anti-tumor mAbs. In this study, we report that tumor-bearing mice treated with a combination of beta-glucan and an anti-tumor mAb show almost complete cessation of tumor growth. This activity evidently derives from a 25-kDa fragment of beta-glucan released by macrophage processing of the parent polysaccharide. This fragment, but not parent beta-glucan, binds to neutrophil CR3, induces CBRM 1/5 neoepitope expression, and elicits CR3-dependent cytotoxicity. These events require phosphorylation of the tyrosine kinase, Syk, and consequent PI3K activation because beta-glucan-mediated CR3-dependent cytotoxicity is greatly decreased by inhibition of these signaling molecules. Thus, beta-glucan enhances tumor killing through a cascade of events, including in vivo macrophage cleavage of the polysaccharide, dual CR3 ligation, and CR3-Syk-PI3K signaling. These results are important inasmuch as beta-glucan, an agent without evident toxicity, may be used to amplify tumor cell killing and may open new opportunities in the immunotherapy of cancer.
Li
Bing
B
Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Allendorf
Daniel J
DJ
Hansen
Richard
R
Marroquin
Jose
J
Ding
Chuanlin
C
Cramer
Daniel E
DE
Yan
Jun
J
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D003179:Complement C3b / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008223:Lymphoma / Q000201:enzymology / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009895:Opsonin Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D016019:Survival Analysis; D000072377:Syk Kinase; D015003:Yeasts / Q000276:immunology; D047071:beta-Glucans / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D047908:Intracellular Signaling Peptides and Proteins; D016177:Macrophage-1 Antigen; D009895:Opsonin Proteins; D047071:beta-Glucans; D003179:Complement C3b; C033363:beta-1,3-glucan; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse