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

描述(申请人提供)：这项建议的总体目标是描述人类对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)类别，在癌细胞中选择性过度表达，并与潜在的恶性肿瘤过程有关。我们已经发现，在不同的癌细胞上，有600多个磷酸肽由MHC-I和MHC-II分子递送。这些磷酸肽中的大多数来自与细胞生长控制和信号传递过程有关的蛋白质，其中许多在癌细胞中处于失控状态。在正常细胞上显示的很少。这些磷酸肽代表了一个新的和独特的癌症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，健康人对某些磷酸肽的免疫反应出奇地强，这是由于已经表现出记忆表型的CD8T细胞。这种预先存在的记忆免疫力在正常人中一般不会出现在其他类型的癌症AGS中，但只有在癌症患者中才明显，而且通常只有在接种疫苗后才会出现。重要的是，在慢性淋巴细胞白血病(CLL)和急性髓系白血病(AML)患者中，对许多磷酸肽的强烈免疫力减弱或缺失。AML患者可以通过异基因供者的骨髓移植恢复它。总体而言，这些结果表明，假设事先暴露于磷酸肽，在没有可识别的癌症和潜在的免疫监测方面，会导致磷酸肽特异性T细胞记忆的发展。此外，癌症进展与未能形成这种类型的免疫力或随着时间的推移而失去这种免疫力有关。然而，还需要更多的工作来确定正常人对与白血病和实体瘤恶性肿瘤相关的更大一组磷肽的先前存在的记忆免疫的存在，并了解其发展的基础。此外，重要的是要了解在其他形式的癌症患者中是否明显缺乏磷酸肽特异性免疫。最后，重要的是要确定癌症患者是否有可能复苏或放大这种免疫。因此，该研究的具体目标是：1)确定正常人对先前存在的记忆的发展是否基于与EBV转化相关的磷肽的反应；2)确定这些癌症患者对选择性表达于白血病和实体肿瘤的MHC相关磷酸肽的免疫状态；3)纵向评估骨髓增生异常综合征(MDS)患者对磷肽的免疫力及其与AML最终发展的关系；4)评估癌症患者的治疗干预措施对恢复或增强对磷肽的免疫反应的能力。这项工作将通过疫苗接种或过继转移方法，可能与其他免疫治疗或化疗方法相结合，为针对癌症相关磷酸肽的临床试验奠定基础。

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.