Mechanism by Which Orally Administered β-1,3-Glucans Enhance the Tumoricidal Activity of Antitumor Monoclonal Antibodies in Murine Tumor Models

Abstract

Antitumor mAb bind to tumors and activate complement, coating tumors with iC3b. Intravenously administered yeast β-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 β-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 β-1,3;1,6-glucan functioned similarly to barley β-1,3;1,4-glucan with antitumor mAb. With both oral β-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 β-1,3-glucan were labeled with fluorescein to track their oral uptake and processing in vivo. Orally administered β-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 β-1,3-glucans into smaller soluble β-1,3-glucan fragments that were taken up by the CR3 of marginated granulocytes. These granulocytes with CR3-bound β-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.

Potentiating Effect of .BETA.-Glucans on Photodynamic Therapy of Implanted Cancer Cells in Mice

“…The antitumor activity of β -glucans is known and has been reported in several studies with fungal (1 3),(1 6)-β -glucan, such as shizophylan, lentinam (Ooi and Liu 2000;Zhang et al 2005), (1 3),(1 6)-β -glucan from yeast (Kiho et al 1998). It can be explained that after implantation of tumor cells naturally elicited antitumor antibodies most probably occur, and they function similarly to exogenous antitumor mAbs by coating tumor cells with iC3b fragments (Hong et al 2004). Moreover, β -glucan converts the nonprotective Th2-type response, which has been reported as dominant in the course of cancer, to a protective Th1-type response that favors cytotoxic T lymphocytes activity (Baran et al 2007).…”

“…The ability of β -glucan to enhance the activity of antitumor monoclonal antibodies (mAbs) also requires that they activate complement and deposit iC3b on tumor cells for recognition by CR3 on granulocytes and NK cells (Cheung and Modak 2002;Hong et al 2003). It has been demonstrated that β -glucan from both barley (Cheung and Modak 2002;Modak et al 2005) and yeast (Yan et al 1999;Hong et al 2003Hong et al , 2004Li et al 2006Li et al , 2007 has synergistic effects when used with anticancer mAbs in various tumor models. The mechanism of action has been explained in several studies (Hong et al 2003(Hong et al , 2004Li et al 2006).…”

“…However, others have reported (Rice et al 2005) that a high concentration of β -glucan appears already 3 h after oral administration. Orally and intravenously administered β -glucan functions by a similar mechanism (Hong et al 2004). Intravenous β -glucan is delivered directly to the CR3 on circulating granulocytes.…”

“…Therefore, β -glucans were administered 24 h before the laser irradiation in our study. The rationale for this timing stems from a previous study, which reported that a minimum of 3 days after oral administration is needed for macrophages to degrade the large molecules of digested β -glucan into smaller active fragments, which primes CR3 on the effector cells (Hong et al 2004). However, others have reported (Rice et al 2005) that a high concentration of β -glucan appears already 3 h after oral administration.…”

“…Intravenous β -glucan is delivered directly to the CR3 on circulating granulocytes. Orally administered high molecular weight β -1,3 glucans, such as glucan from baker's yeast and barley (Hong et al 2004), or small molecular weight β -1,3 glucans, such as laminarin (Rice et al 2005), go through an intermediate step in which they are taken up by gastrointestinal macrophages and shuttled to reticuloendothelial tissue and bone marrow. Once there, macrophages degrade large molecules of β -glucan into smaller biologically active fragments (Li et al 2006).…”