Yeast Beta-Glucan Amplifies Phagocyte Killing of iC3b-Opsonized Tumor Cells via Complement Receptor 3-Syk-Phosphatidylinositol 3-Kinase Pathway1
The Journal of Immunology, 2006, 177: 1661-1669.
Copyright © 2006 by The American Association of Immunologists.
Bing Li2, Daniel J. Allendorf2, Richard Hansen, Jose Marroquin,
Chuanlin Ding, Daniel E. Cramer and Jun Yan3
Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202
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 ß-glucan, a polysaccharide produced by fungi, yeast, and grains, but not mammalian cells. ß-glucans are bound by C receptor 3 (CR3) and, in concert with target-associated complement fragment iC3b, elicit phagocytosis and killing of yeast. ß-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 ß-glucan and an anti-tumor mAb show almost complete cessation of tumor growth. This activity evidently derives from a 25-kDa fragment of ß-glucan released by macrophage processing of the parent polysaccharide. This fragment, but not parent ß-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 ß-glucan-mediated CR3-dependent cytotoxicity is greatly decreased by inhibition of these signaling molecules. Thus, ß-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 in as much as ß-glucan, an agent without evident toxicity, may be used to amplify tumor cell killing and may open new opportunities in the immunotherapy of cancer.
Published at wellmune.com on 19 August 2006