Dendritic Cell Biology and Therapy

该项目是之前项目 1 和 2 中进行的研究的延续。我们获得了证据 辅助 T 细胞对 MUC1 肿瘤抗原肽的反应和抗体反应在 MUCITg 小鼠与 WT 小鼠相比，但当肽携带 0 连接的 GalNac 残基时，代表 MUC1 的低糖基化肿瘤形式、MUCITg 小鼠的反应与 WT 小鼠相同。我们 假设 DC 呈现的 MUC1 肽与糖肽的反应差异为 由于耐受性，因为 MUC1 肽被视为“自身”，而肿瘤特异性糖肽代表 异常的自我，因此被视为外国人。类似的耐受状态可能是 MUC1 肽的特征 患者体内存在特异性 T 细胞，因此相关假设是 MUC1 糖肽是一种更好的疫苗 比迄今为止已使用的肽更候选。我们的第三个假设是免疫参数 功效（生物标志物）作为 DC 和 T 细胞免疫激活的复杂特征而存在，我们的目标是 以确定那些可以预测 MUC1 疫苗抗肿瘤功效的疫苗。我们建议检验这些假设 在人类 MUC1 转基因小鼠和 MUC1 肽和糖肽特异性 TCR 转基因小鼠中，以及 如在恒河猴中使用恒河猴 MUC1 序列。我们提出以下具体目标： 具体 目标 1：我们将确定哪些因素控制对自身/肿瘤抗原 MUC1 的免疫反应差异 当使用 MUC1 肽（自身？）与 MUC1 糖肽（外来？）作为抗原时，MUCITg 小鼠 靶向佐剂激活的 DC。具体目标2：我们将在恒河猴中测试不同的MUC1疫苗 拟议的实验将借鉴项目 1 和 3 中已经进行或即将进行的观察 识别 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。能够引发具有预定特征的免疫反应 的抗肿瘤功效。

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.