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

描述（由申请人提供）：我们强有力的初步数据证明了一种新的肿瘤治疗策略，即通过白细胞补体受体3（CR 3，CD 11b/CD 18，α M β 2-整联蛋白）杀死经iC 3b调理的肿瘤细胞。在多种小鼠同源肿瘤模型中，酵母β-葡聚糖与抗肿瘤单克隆抗体联合使用可获得治疗效果。长期目标是了解酵母β-葡聚糖介导的肿瘤免疫治疗的分子和细胞作用机制，然后促进其与人源化抗肿瘤mAb或肿瘤疫苗的临床应用，引发足够的体液应答以激活补体。我们进一步证明酵母颗粒β-葡聚糖刺激树突状细胞上调表面共刺激分子和MHC II类表达以及IL-12和TNF-α的分泌。此外，β-葡聚糖和MUC 1疫苗的联合治疗显示出对肿瘤消退的协同作用。本提案中要检验的主要假设是：1）酵母颗粒β-葡聚糖通过分泌细胞因子和增强树突状细胞抗原呈递来增强适应性免疫; 2）酵母β-葡聚糖对发生自发性乳腺癌的MUC 1/MT双Tg小鼠中的B细胞介导的MUC 1疫苗具有协同治疗作用。目的1确定β-葡聚糖介导的肿瘤免疫疗法是否通过使用过继转移的OVA TCR转基因OT-I（CDS）和/或OT-II T细胞（CD 4）促进适应性T和B细胞应答。将确定β-葡聚糖增强的树突细胞抗原呈递和随后增强的抗原特异性T细胞应答。目的2：利用B细胞介导的MUC 1疫苗联合β-葡聚糖，研究MUC 1/MT双Tg小鼠自发性乳腺癌的治疗效果。将肿瘤相关抗原MUC 1靶向B细胞破坏MUC 1 Tg小鼠中的T和B细胞耐受性。将确定β-葡聚糖对抗MUd T和B细胞应答的增强作用。β-葡聚糖介导的免疫疗法在治疗环境中显示出有希望的结果，并且对癌症患者具有潜在的治疗作用。

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.