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

基本信息

批准号：
10667446
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
项目类别：
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/10667446
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 Knockout Mice 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 Translational Research Tumor Escape Viral Virus 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 treatment and outcome tumor tumor progression

项目摘要

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和病毒的主要机制被感染的细胞。 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 MHC I 分子上展示的肽。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 抗原呈递，使其更难检测，和/或通过表达分子，例如 PDL1，抑制攻击性 T 细胞。因此，了解肿瘤发生的机制非常重要。这些过程失调，这如何影响癌症进展和免疫治疗，以及如何逆转免疫逃避以改善结果——这些是该提案的总体目标。我们的建议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 MHC I 抗原呈递的正调节因子和 PDL1 (CD274) 表达的负调节因子。我们的第一个目标将测试 IRF2 表达缺失是癌症逃逸方式之一的假设免疫监视和控制进展，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 的缺失会损害免疫疗法的成功，并且 IRF2 将提供急需的生物标志物来识别患者是否会从免疫治疗中受益。这这一假设的合理性在于，IRF2 缺失导致 MHC I 抗原呈递减少，损害 CD8 T 细胞反应的能力，而检查点封锁会增强 CD8 T 细胞反应的能力，以发现并杀死它们癌症目标。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所致。我们的目标是确定 IRF2 表达缺失的根本机制并开发方法逆转由 IRF2 缺失引起的免疫逃避，可以转化为未来的临床试验。我们的实验方法将使用 IRF2 功能获得和功能丧失模型，以及人源化和 IRF2 KO 小鼠以确定 IRF2 在肿瘤免疫逃避和免疫治疗反应中的作用对人类和小鼠癌症（黑色素瘤、非小细胞肺癌和 MCA 肉瘤）进行检查点阻断。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过程和/或对免疫治疗的反应。支持我们的假设和可行性所提出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、seq 技术、抑制剂和细胞因子来阐明 IRF2 表达如何丢失以及如何避免这种丢失用于治疗。