Role of IRF2 in cancer immune evasion and immunotherapy

IRF2在癌症免疫逃避和免疫治疗中的作用

• 批准号: 10414938
• 负责人: KENNETH L ROCK
• 金额: $ 57.12万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-29 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414938
• 关键词: Affect; Antigen Presentation; Basic Science; Bioinformatics; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Clinical; Clinical Trials; Data; Development; Epigenetic Process; FDA approved; Failure; Future; Genetic Screening; Goals; Human; I-antigen; IRF1 gene; Immune; Immune Evasion; Immune response; Immune system; Immunologic Surveillance; Immunotherapy; Impairment; Investigation; Knockout Mice; Lead; Malignant Neoplasms; Modeling; Molecular; Mus; Non-Small-Cell Lung Carcinoma; Outcome; Patients; Peptides; Phenotype; Process; Prognosis; Resistance; Role; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic Agents; Therapeutic Uses; Translating; Treatment outcome; Tumor Escape; Viral; Virus; base; cancer cell; cancer immunotherapy; cancer type; clinical predictors; cytokine; epigenetic silencing; experimental study; gain of function; immune checkpoint blockade; immune clearance; immunogenic; improved; improved outcome; inhibitor; insight; loss of function; lung sarcoma; melanoma; mutant; novel marker; novel therapeutics; pre-clinical; programmed cell death ligand 1; response; sarcoma; success; transcription factor; translational study; tumor; tumor progression

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.

抽象的 CD8 T淋巴细胞是免疫系统消除癌症并病毒的主要机制 感染细胞。 CD8 T细胞通过识别免疫原性（例如病毒或突变体）来检测这些异常靶标 在MHC I分子上显示的肽。癌症和病毒可以通过 抑制MHC I抗原表现，使它们难以检测和/或通过表达分子，例如 PDL1，抑制攻击T细胞。因此，了解肿瘤的机制很重要 失调这些过程，这如何影响癌症的进展和免疫疗法，以及如何逆转 免疫逃避以改善结果 - 这些是该提议的总体目标。我们的建议是基于 我们在公正的转发遗传筛选中发现了转录因子IRF2，这是一个意外的是 MHC I抗原表现的阳性调节剂和PDL1（CD274）表达的负调节剂。我们的 第一个目标将检验以下假设，即IRF2失去表达是癌症逃脱的方式之一 免疫监视和控制以进行进展，这与临床结果较差有关。我们的 第二个目的将检验以下假设，即IRF2的丧失会损害免疫疗法的成功和IRF2 将提供急需的生物标志物，以识别将受益于免疫疗法的患者。这 该假设的理性是，由IRF2丢失引起的MHC I抗原表现的减少将 损害CD8 T细胞响应的能力，该反应通过检查站封锁而为查找和杀死其杀戮的能力 癌症靶标。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引起的。我们的 目标是确定损失IRF2表达的基本机制，并开发出 扭转可以转化为未来临床试验的IRF2损失引起的免疫逃避。我们的 实验方法将使用IRF2功能和功能模型的丧失以及人性化的功能模型的丧失 和IRF2 KO小鼠定义IRF2在肿瘤免疫中的作用和对免疫疗法的反应 与人类和小鼠癌（黑色素瘤，NSCLC和MCA肉瘤）的检查点封锁。我们将 将这些发现转化为人类癌症患者，评估IRF2是否是可以预测的生物标志物 临床病程和/或对免疫疗法的反应。支持我们的假设和可行性 建议的实验由强大的初步数据支持。最后，我们将使用生物信息学，SEQ 技术，抑制剂和细胞因子阐明IRF2表达如何丢失以及如何避免这种损失 用于治疗。