Role of IRF2 in cancer immune evasion and immunotherapy

摘要 CD8T淋巴细胞是免疫系统清除癌症和病毒的主要机制 被感染的细胞。CD8T细胞通过识别免疫原性(如病毒或突变)来检测这些异常靶点 显示在MHC I分子上的多肽。癌症和病毒可以通过以下方式逃避免疫控制和消除 抑制MHC I抗原提呈，使其更难被检测，和/或通过表达分子，如 PDL1，抑制攻击T细胞。因此，了解肿瘤的发病机制非常重要。 这些过程的失调，如何影响癌症的进展和免疫治疗，以及如何逆转 免疫回避以改善结果--这些是这项提案的总体目标。我们的建议是基于 我们在无偏见的正向遗传筛选中发现了一种转录因子IRF2，它出人意料地是一种 MHC I抗原提呈的正调节因子和PDL1(CD274)表达的负调节因子。我们的 First Aim将测试IRF2表达缺失是癌症逃逸途径之一的假设 免疫监测和控制的进展，这与较差的临床结果相关。我们的 第二个目标将检验以下假设：IRF2基因的缺失会损害免疫治疗的成功，IRF2基因的缺失 将提供一个亟需的生物标记物来识别哪些患者将从免疫治疗中受益或不受益。这个 这一假说的合理性是，由于IRF2的缺失而导致的MHC I抗原提呈减少，将 削弱CD8 T细胞反应被检查点封锁激活的能力，以发现并杀死其 癌症靶点。我们的第三个目标假设IRF2表达的丧失是由于表观遗传沉默。我们的 目的是确定IRF2表达缺失的潜在机制，并开发方法 逆转IRF2缺失导致的免疫逃避，这可以转化为未来的临床试验。我们的 实验方法将使用IRF2功能增益和功能损失模型，并结合人性化 和IRF2 KO小鼠，以确定IRF2在肿瘤免疫逃避和免疫治疗反应性中的作用 对人类和小鼠癌症(黑色素瘤、非小细胞肺癌和大脑中动脉肉瘤)实施检查点封锁。我们会 将这些发现转化为人类癌症患者，评估IRF2是否是可以预测 临床病程和/或对免疫治疗的反应性。支持我们的假设和 拟议的实验得到了强有力的初步数据的支持。最后，我们将使用生物信息学 技术、抑制剂和细胞因子阐明IRF2的表达是如何丢失的以及如何避免这种丢失 接受治疗。

Abstract CD8 T lymphocytes are the major mechanism by which the immune system eliminates cancers and virally infected cells. CD8 T cells detect these abnormal targets by recognizing immunogenic (e.g. viral or mutant) peptides displayed on MHC I molecules. Cancers and viruses can evade immune control and elimination by inhibiting MHC I antigen presentation, making them harder to detect, and/or by expressing molecules, such as PDL1, that inhibit attacking T cells. Therefore, it is important to understand the mechanisms by which tumors dysregulate these processes, how this affects cancer progression and immunotherapy, and how to reverse the immune evasion to improve outcomes - these are the overall goals of this proposal. Our proposal is based on our discovery in an unbiased forward genetic screen, of a transcription factor, IRF2, that unexpectedly is a positive regulator of MHC I antigen presentation and a negative regulator of PDL1 (CD274) expression. Our first aim will test the hypotheses that loss of expression of IRF2 is one of the ways that cancers escape immune surveillance and control to progress and that this is associated with worse clinical outcomes. Our second aim will test the hypotheses that the loss of IRF2 impairs the success of immunotherapy and that IRF2 will provide a much-needed biomarker to identify patients who would benefit, or not, from immunotherapy. The rational for this hypothesis is that the reduction in MHC I antigen presentation caused by loss of IRF2, will impair the ability of CD8 T cell responses that are invigorated by checkpoint blockade to find and kill their cancer targets. Our third aim hypothesizes that the loss of IRF2 expression is due to epigenetic silencing. Our goal is to determine the underlying mechanism for loss of IRF2 expression and to develop approaches to reverse the immune evasion caused by the loss of IRF2 that can be translated into future clinical trials. Our experimental approaches will use IRF2 gain of function and loss of function models, together with humanized and IRF2 KO mice to define the role of IRF2 in tumor immune evasion and responsiveness to immunotherapy with checkpoint blockade for both human and mouse cancers (Melanoma, NSCLC, & MCA sarcomas). We will translate these findings into human cancer patients, evaluating whether IRF2 is a biomarker that can predict clinical course and/or responsiveness to immunotherapy. Support for our hypotheses and feasibility of the proposed experiments are supported by strong preliminary data. Finally, we will use bioinformatics, seq techniques, inhibitors and cytokines to elucidate how IRF2 expression is lost and how to circumvent this loss for therapy.