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.

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 β-glucan, a polysaccharide produced by fungi, yeast, and grains, but not mammalian cells. β-Glucans are bound by C 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. In this study, 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-kDa fragment of β-glucan released by macrophage processing of the parent polysaccharide. This fragment, but not parent β-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 β-glucan-mediated CR3-dependent cytotoxicity is greatly decreased by inhibition of these signaling molecules. Thus, β-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 β-glucan, an agent without evident toxicity, may be used to amplify tumor cell killing and may open new opportunities in the immunotherapy of cancer.

An ∼8400 cal yr record of vegetation change from the northern Peten, Guatemala, provides new insights into the environmental history of the archaeological area known as the Mirador Basin. Pollen, loss on ignition, and magnetic susceptibility analyses indicate warm and humid conditions in the early to mid-Holocene. Evidence for a decrease in forest cover around 4600 cal yr B.P. coincides with the first appearance of Zea mays pollen, suggesting that human activity was responsible. The period between 3450 cal yr B.P. and 1000 cal yr B.P. is characterized by a further decline in forest pollen types, includes an abrupt increase in weedy taxa, and exhibits the highest magnetic susceptibility values since the early Holocene, all of which suggest further agricultural disturbance in the watershed. A brief drop in disturbance indicators around 1800 cal yr B.P. may represent the Preclassic abandonment of the area. Changing pollen frequencies around 1000 cal yr B.P. indicate a cessation of human disturbance, which represents the Late Classic collapse of the southern Maya lowlands.

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Purpose: The beneficial properties of β-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 for eliciting complement receptor 3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether β-glucan therapy has any effect on antitumor adaptive T-cell responses.Experimental Design: We first examined the trafficking of orally administered particulate yeastderived β-glucan and its interaction with dendritic cells (DC) that captured tumor materials. Antigenspecific T cells were adoptively transferred into recipient mice to determine whether oral β-glucan therapy induces augmented T-cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral β-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined.Results: Orally administered particulate β-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced on β-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, β-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment.Conclusions: These data highlight the ability of yeast-derived β-glucan to bridge innate and adaptive antitumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy. Clin Cancer Res; 16(21); 5153-64. ©2010 AACR.