Rebalancing protein homeostasis enhances tumor antigen presentation

项目总结/摘要 癌症是通过遗传和表观遗传变化的结合而产生的， 永生，但同时产生外来抗原，这应该使肿瘤细胞可检测 并将其作为破坏目标。尽管取得了显著的成功， 尽管靶向内源性效应T细胞的免疫疗法已被广泛应用，但许多癌症仍然逃避免疫识别。 成功的免疫疗法的一个关键组成部分是通过主要的抗原递呈途径进行稳健的抗原递呈。 I类组织相容性复合物（MHC-I）[10，15，34]。由于抗原可以从突变体中获得， 由于蛋白质组存在于癌症中，因此可以预期具有高突变负荷的肿瘤类型，如 肺腺癌（LUAD）的特征在于强T细胞应答。然而，许多患者 这些肿瘤类型要么对免疫疗法没有反应，要么在初始治疗后复发。 恶性转化的内在原因是由于蛋白质的积累而诱导蛋白毒性应激。 突变的、构象异常的蛋白质[5]。为了克服这些压力，癌细胞 精确地依赖于分子伴侣[28]。这种现象表明免疫原性 由来源于癌症中异常基因组和表观基因组的抗原产生的免疫抑制作用被 分子伴侣的功能和蛋白质折叠机制。因此，我假设蛋白质的诱导剂 错误折叠应激导致MHC-I分子的抗原呈递增加， 免疫原性 我建议探索LUAD突变蛋白质组不稳定的影响， 让宿主的免疫系统知道其目标如下： 目的1：分析蛋白质错误折叠应激对MHC-I抗原提呈的影响 分子。在这一目标中，我将询问亚毒性剂量的小分子调节剂的影响， 蛋白质折叠对人和鼠LUAD细胞系中抗原呈递的影响。我们希望揭露 突变蛋白质组对免疫系统的作用而不破坏蛋白质折叠机制 功能协调发展的另外，我会从遗传学和免疫学的角度扰乱 介绍，以了解调节蛋白毒性应激放大的机制， 并使LUAD细胞系中的抗原呈递多样化。 目的2：分析HSP90 i和其他蛋白毒性应激诱导物在高突变性肝癌中的作用。 小鼠肺腺癌模型 将测试用细胞质蛋白毒性应激调节剂进行低剂量处理的能力， 在LUAD超突变小鼠模型中刺激抗肿瘤应答。 该提案将突出机械新颖的策略，以驱动抗肿瘤免疫反应。

PROJECT SUMMARY / ABSTRACT Cancers arise through a combination of genetic and epigenetic changes that facilitate their immortality, but simultaneously create foreign antigens, which should render neoplastic cells detectable by the immune system and target them for destruction. Despite the remarkable success of immunotherapies targeting endogenous effector T-cells, many cancers still evade immune recognition. A critical component of successful immunotherapy is robust antigen presentation through Major Histocompatibility Complex Class I (MHC-I) [10, 15, 34]. Since antigens can be derived from the mutant proteome present in cancers, it would be expected that tumor types with high mutational load, such as lung adenocarcinoma (LUAD), are characterized by strong T cell responses. However, many patients with these tumor types either fail to respond to immunotherapy, or relapse after initial treatment. Inherent to malignant transformation is the induction of proteotoxic stress due to the accumulation of mutated, conformationally aberrant proteins [5]. To overcome these stresses, cancer cells are exquisitely dependent on molecular chaperones [28]. This phenomenon suggests that immunogenicity generated by antigens derived from the aberrant genome and epigenome in cancer is dampened by the function of chaperones and the protein folding machinery. Thus, I hypothesize that inducers of protein misfolding stress lead to increased antigen presentation by MHC-I molecules and increased immunogenicity. I propose to explore the impact of destabilizing the mutant proteome of LUAD in order to reveal it to the host’s immune system. The aims are as follows: Aim 1: Analyze the impact of protein misfolding stress on antigen presentation by MHC-I molecules. In this aim I will interrogate the impact of subtoxic doses of small molecule modulators of protein folding on antigen presentation in human and murine LUAD cell lines. We expect to expose the mutant proteome to the immune system without disrupting protein folding machineries essential functions. Additionally, I will genetically and pharmacologically perturb the pathways involved in antigen presentation, in order to understand the mechanisms by which modulators of proteotoxic stress amplify and diversify antigen presentation in LUAD cell lines. Aim 2: Analyze the role of HSP90i and other inducers of proteotoxic stress in a hyper-mutational mouse model of lung adenocarcinoma (LUAD) Low-dose treatment with modulators of cytoplasmic proteotoxic stress will be tested for their ability to stimulate an anti-tumor response in a hyper-mutational mouse model of LUAD. This proposal will highlight mechanistically novel strategies to drive anti-tumor immune responses.