Abstract: Anti-tumor monoclonal antibodies (mAbs) hold promise for cancer therapy but are relatively inefficient. Therefore, there is a need for agents which might amplify the effectiveness of these mAbs. One such agent is β-glucan, a polysaccharide produced by fungi, yeast and grains but not mammalian cells. β-Glucans are bound by complement receptor 3 (CR3) and, in concert with target-associated complement fragment iC3b elicit phagocytosis and killing of yeast. β-Glucans may also promote killing of iC3b-opsonized tumor cells engendered by administration of anti-tumor mAbs. Here, we report that tumor bearing mice treated with a combination of β-glucan and an anti-tumor mAb show almost complete cessation of tumor growth. This activity evidently derives from a 25 kD fragment of β-glucan released by macrophage (Mφ) processing of the parent polysaccharide. This fragment - but not parent β-glucan - binds to neutrophil CR3, induces CBRM1/5 neoepitope expression, and elicits CR3-dependent cytotoxicity. These events require phosphorylation of the tyrosine kinase, Syk, and consequent phosphatidylinositol 3-kinase (PI 3-kinase) activation because β-glucan-mediated CR3-dependent cytotoxicity is greatly decreased by inhibition of these signaling molecules. Thus, β-glycan enhances tumor killing through a cascade of events including in vivo Mφ cleavage of the polysaccharide, dual CR3 ligation and CR3-Syk-PI3-kinase signaling.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]