Dendritic Cell Biology and Therapy

这个项目是在之前项目1和2中进行的研究的继续。我们获得了证据 对MUC1肿瘤抗原肽的辅助T细胞反应和抗体反应在 MUCITg小鼠与WT小鼠相比，但当多肽携带0-连接的GalNAc残基时，代表 低糖肿瘤形式的MUC1，MUCITg小鼠的反应与WT小鼠一样好。我们 假设DC提出的对MUC1多肽和糖肽的反应差异为 由于耐受性，因为MUC1肽被认为是“自我”，而肿瘤特异性糖肽代表 不正常的自我，因此被认为是外来的。类似的耐受状态可能是MUC1多肽的特征 患者的特异性T细胞，因此一个相关的假设是MUC1糖肽是更好的疫苗 比目前已经使用的多肽更有可能成为候选。我们的第三个假设是免疫参数 (生物标记物)作为DC和T细胞免疫激活的复杂信号而存在，我们的目标是 目的：寻找能够预测MUC1疫苗抗肿瘤效果的基因。我们建议对这些假设进行检验 在人MUC1转基因小鼠和MUC1多肽和糖肽特异性TCR转基因小鼠中 与使用恒河猴MUC1序列的恒河猴一样。我们提出了以下具体目标： 目的1：我们将确定是什么控制对自身/肿瘤抗原MUC1的免疫反应的差异 当MUCITg小鼠的MUC1肽(自身？)与MUC1糖肽(外来？)被用作抗原和 针对佐剂激活的DC。具体目标2：我们将在恒河猴身上测试不同的MUC1疫苗 拟议的实验将利用在项目1和项目3中已经进行或将要进行的观察。 确定T细胞和DC激活的重要参数。项目2的最终目标是定义 下一代MUC1疫苗。能够诱导具有预定特征的免疫反应 抗肿瘤的功效。

This project is a continuation of studies performed in the previous Projects 1 and 2. We obtained evidence that helper T cell responses and antibody responses to the MUC1 tumor antigen peptide are reduced in MUCITg mice compared to WT mice but when the peptide carried 0-linked GalNac residues, representing hypoglycosylated tumor form of MUC1, MUCITg mice responded equally well as the WT mice. We hypothesize that the difference in responses to the MUC1 peptide versus glycopeptide presented by DC is due to tolerance because MUC1 peptide is perceived as "self," while tumor-specific glycopeptide represents abnormal self and thus is perceived as foreign. Similar state of tolerance may characterize MUC1 peptide specific T cells in patients and thus a related hypothesis is that MUC1 glycopeptide is a better vaccine candidate than the peptide that has been used to date. Our third hypothesis is that immune parameters (biomarkers) of efficacy exist as complex signatures of immune activation of DC and T cells and our goal is to identify those that can predict anti-tumor efficacy of MUC1 vaccines. We propose to test these hypotheses in human MUC1 transgenic mice and MUC1 peptide and glycopeptide specific TCR transgenic mice, as well as in rhesus macaques using rhesus MUC1 sequences. We propose the following specific aims: Specific Aim 1: We will determine what controls differences in immune responses to the self/tumor antigen MUC1 in MUCITg mice when MUC1 peptide (self?) versus MUC1 glycopeptide (foreign?) are used as antigens and targeted to adjuvant-activated DC. Specific Aim 2: We will test different MUC1 vaccines in rhesus macaques The proposed experiments will draw on observations already made or to tte made in the Projects 1 and 3 that identify important parameters of T cell and DC activation. The ultimate goal of Project 2 is to define the next generation of MUC1 vaccines.capable of eliciting an immune response with a predetermined signature of anti-tumor efficacy.