Immunity to MHC-restricted phosphopeptides in healthy donors and cancer patients

描述（由申请人提供）：本申请的总体目标是表征人类对mhc相关磷酸肽的免疫反应，mhc相关磷酸肽是一种新的癌症抗原（Ag），在癌细胞中选择性过表达，并与恶性肿瘤的基础过程相关。我们已经发现超过600种磷酸肽由MHC-I和MHC-II分子呈现在不同的癌细胞上。这些磷酸肽大部分来自与细胞生长控制和信号传导过程有关的蛋白质，其中许多在癌细胞中是失调的。很少显示在正常细胞上。这些磷酸肽代表了一种新的和独特的癌症Ags集合，将被理解和开发用于癌症免疫治疗。我们最近还发现，健康个体对某些磷酸肽的免疫反应异常强烈，这是由于CD8 T细胞已经表现出记忆表型。这种预先存在的记忆免疫通常在正常个体中对其他类型的癌症Ags没有观察到，但只有在癌症患者中才明显，而且通常只有在接种疫苗后。重要的是，慢性淋巴细胞白血病（CLL）和急性髓性白血病（AML）患者对许多磷酸肽的强免疫减弱或缺失。急性髓系白血病患者可通过异基因供体骨髓移植恢复。总的来说，这些结果表明，先前暴露于磷酸肽，在没有可识别的癌症和潜在的免疫监视方面，导致磷酸肽特异性T细胞记忆的发展。此外，癌症的进展与这种类型的免疫力未能发展或随着时间的推移而丧失有关。然而，需要更多的工作来确定正常个体对与白血病和实体瘤恶性肿瘤相关的大量磷酸肽存在预先存在的记忆免疫，并了解其发展的基础。此外，了解其他形式的癌症患者是否明显缺乏磷酸肽特异性免疫也很重要。最后，确定在癌症患者中这种免疫是否可能复苏或扩增是很重要的。因此，具体目的是：1)确定正常人既存记忆的发展是否基于对与EBV转化相关的磷酸肽的反应；2)检测白血病和实体肿瘤患者对选择性表达的mhc相关磷酸肽的免疫状况；3)纵向评价骨髓增生异常综合征（MDS）患者对磷酸肽的免疫及其与AML最终发展的关系；4)评估治疗干预对肿瘤患者复苏或增强对磷酸肽免疫反应的能力。这项工作将为通过疫苗接种或过继性转移方法靶向癌症相关磷酸肽的临床试验奠定基础，并可能与其他免疫治疗或化疗方式相结合。

DESCRIPTION (provided by applicant): The Overall Goal of this proposal is to characterize human immune responses to MHC-associated phosphopeptides, a new category of cancer antigens (Ag) that are selectively overexpressed in cancer cells and linked to processes that underlie malignancy. We have discovered over 600 phosphopeptides are presented by MHC-I and MHC-II molecules on different cancer cells. Most of these phosphopeptides come from proteins that have been linked to cellular growth control and signaling processes, many of which are disregulated in cancer cells. Very few are displayed on normal cells. These phosphopeptides represent a novel and unique collection of cancer Ags to be understood and exploited for cancer immunotherapy. We have also recently discovered that immune responses to some phosphopeptides in healthy individuals are surprisingly strong and are due to CD8 T cells that already show a memory phenotype. This pre-existing memory immunity is not generally observed to other kinds of cancer Ags in normal individuals, but is only evident in cancer patients, and often only after vaccination. Importantly, strong immunity to many phosphopeptides was diminished or absent in patients with chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). It could be restored in AML patients by bone marrow transplantation from an allogeneic donor. Overall, these results suggest the hypothesis that prior exposure to phosphopeptides, in the absence of discernible cancer and potentially as an aspect of immune surveillance, leads to the development of phosphopeptide-specific T cell memory. Furthermore, cancer progression is associated with failure to develop this type of immunity, or its loss over time. However, much additional work is needed to establish the existence of pre-existing memory immunity in normal individuals to a larger cohort of phosphopeptides associated with leukemias and solid tumor malignancies, and to understand the basis for its development. In addition, it is important to understand whether lack of phosphopeptide-specific immunity is evident in patients with other forms of cancer. Finally, it is important to determine whether resuscitation or amplification of this immunity is possible in cancer patients. Accordingly, the Specific Aims are: 1) To determine whether the development of pre-existing memory in normal individuals is based on responses to phosphopeptides associated with EBV transformation; 2) To determine the status of immunity to MHC-associated phosphopeptides selectively expressed on leukemias and solid tumor malignancies in patients with these cancers; 3) To longitudinally evaluate immunity to phosphopeptides in myelodysplastic syndrome (MDS) patients, and its association with the eventual development of AML; 4) To evaluate the ability of therapeutic interventions in cancer patients to resuscitate or augment immune responses to phosphopeptides. This work will set the stage for clinical trials targeting cancer-associated phosphopeptides through vaccination or adoptive transfer approaches, potentially combined with other immunotherapeutic or chemotherapeutic modalities.