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: 10204986
• 负责人: KENNETH L ROCK
• 金额: $ 58.29万
• 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/10204986
• 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/antagonist; 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.

摘要 CD 8 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CD 8 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分子上展示的肽。癌症和病毒可以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，如 PDL 1，抑制攻击性T细胞。因此，重要的是要了解肿瘤的机制， 这些过程失调，这如何影响癌症进展和免疫治疗，以及如何逆转这些过程。 免疫逃避，以改善结果-这些都是这个建议的总体目标。我们的建议是基于 我们在无偏正向遗传筛选中发现了一种转录因子IRF 2， MHC I抗原呈递的正调节剂和PDL 1（CD 274）表达的负调节剂。我们 第一个目标是检验IRF 2表达缺失是癌症逃逸途径之一的假设 免疫监视和控制进展，这与更糟糕的临床结果有关。我们 第二个目标是检验IRF 2的缺失会损害免疫治疗的成功， 将提供一个急需的生物标志物，以确定患者谁会受益，或没有，从免疫治疗。的 这一假设的合理性在于，IRF 2缺失导致的MHC I抗原呈递的减少， 削弱CD 8 T细胞应答的能力，这些应答被检查点阻断所抑制，以发现和杀死它们的免疫原。 癌症靶点我们的第三个目标假设IRF 2表达的丧失是由于表观遗传沉默。我们 目标是确定IRF 2表达丧失的潜在机制并开发方法 逆转由IRF 2缺失引起的免疫逃避，这可以转化为未来的临床试验。我们 实验方法将使用IRF 2功能获得和功能丧失模型，以及人源化的 和IRF 2 KO小鼠，以确定IRF 2在肿瘤免疫逃避和对免疫治疗的反应性中的作用 用于人类和小鼠癌症（黑色素瘤、NSCLC和MCA肉瘤）的检查点阻断。我们将 将这些发现转化为人类癌症患者，评估IRF 2是否是一种可以预测 临床过程和/或对免疫疗法的反应性。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IRF 2表达如何丢失以及如何避免这种丢失 治疗