Ligation of CR3 by Glucan and iC3b Links Innate and Adaptive Anti-tumor Immunity

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DESCRIPTION (provided by applicant): Our strong preliminary data demonstrate a novel therapeutic strategy for tumor therapy by engaging leukocyte complement receptor 3 (CR3, CD11b/CD18, alphaMbeta2-integrin) to kill tumor cells opsonized with iC3b. Therapeutic efficacy is achieved by using yeast beta-glucan in combination with anti-tumor mAbs in multiple mouse syngeneic tumor models. The long-term goal has been to understand the molecular and cellular mechanisms of action within yeast beta-glucan mediated tumor immunotherapy, and then promote it for clinical utilization with humanized anti-tumor mAbs or tumor vaccines eliciting a sufficient humoral response for activation of complement. We further demonstrate that yeast particulate beta-glucan stimulates dendritic cells for up-regulation of surface co-stimulatory molecules and MHC class II expression and secretion of IL-12 and TNF-alpha. Moreover, combined therapy of beta-glucan and MUC1 vaccine exhibits a synergistic effect on tumor regression. The central hypotheses to be tested in this proposal are: 1) yeast particulate beta-glucan enhances the adaptive immunity via secretion of cytokines and the enhanced dendritic cell antigen presentation; and 2) yeast beta-glucan has a synergistically therapeutic effect on a B cell-mediated MUC1 vaccine in MUC1/MT double Tg mice developing spontaneous mammary carcinoma. Aim 1 determines whether beta-glucan mediated tumor immunotherapy promotes the adaptive T and B cell responses by using adoptively transferred OVA TCR transgenic OT-I (CDS) and/or OT-II T cells (CD4). The enhanced dendritic cell antigen presentation and subsequent enhanced antigen-specific T cell responses by beta-glucan will be determined. Aim 2 uses a B cell-mediated MUC1 vaccine in combination with beta-glucan to investigate the therapeutic efficacy in MUC1/MT double Tg mice developing spontaneous mammary carcinoma. Targeting tumor-associated antigen MUC1 to B cells breaks T and B cell tolerance in MUC1 Tg mice. The enhancing effect of beta-glucan on anti-MUd T and B cell responses will be determined. Beta-glucan mediated immunotherapy demonstrates promising results in the therapeutic setting and is potentially remedial for cancer patients.