T cell expressed miR-155 promotes antitumor immunity and immune checkpoint blockade responses in colon cancer through repression of Ship1

T 细胞表达的 miR-155 通过抑制 Ship1 促进结肠癌的抗肿瘤免疫和免疫检查点阻断反应

• 批准号: 10376035
• 负责人: WILLIAM WEIHAO TANG
• 金额: $ 4.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376035
• 关键词: Address; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Compartmentation; Cell Death; Cells; Cellular biology; Clinical; Colon; Colon Adenocarcinoma; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Cytotoxic T-Lymphocytes; DNA; Data; Data Set; Death Rate; Disease; Environment; Exclusion; Fibrosis; Frequencies; Gene Expression; Genes; Goals; Grant; Human; Immune; Immune Targeting; Immune response; Immunity; Immunologic Markers; Immunophenotyping; Immunotherapy; Incidence; Infection; Infiltration; Inflammatory; Interferon Type II; Intrinsic factor; Low-Frequency Microsatellite Instability; Malignant Neoplasms; Mediating; MicroRNAs; Microsatellite Instability; Minority; Mismatch Repair Deficiency; Modeling; Mus; Outcome; PD-1 inhibitors; Patient-Focused Outcomes; Patients; Production; Prognosis; Repression; Research; Resistance; Solid Neoplasm; Standardization; Survival Rate; T cell regulation; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; The Cancer Genome Atlas; Therapeutic; Tumor Burden; Tumor Immunity; Tumor-infiltrating immune cells; United States; Untranslated RNA; Work; adaptive immune response; anti-PD1 therapy; anti-tumor immune response; base; cell growth; colon cancer patients; effective therapy; genetic signature; immune checkpoint blockade; improved; improved outcome; in vivo; innovation; melanoma; metastatic colorectal; mortality; mouse model; neoantigens; neoplastic cell; new therapeutic target; patient response; patient subsets; pembrolizumab; polarized cell; response; screening; standard of care; therapeutic target; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the second deadliest cancerglobally and has the third-highest incidenceand mortality rate of all cancers in the United States. Patients under 50 years old are increasingly presenting with advanced- stage CRC, which has a five-year survival rate of 14% with the current standard of care. Thus, new treatment options, such as immune checkpoint blockade (ICB), are being explored. T cell inactivation often occurs in tumors, leading to a poor immune response. ICB often induces a robust antitumor immune response by blocking T cell inactivation in patients with microsatellite instability-high (MSI-H) metastatic CRC. This high response rate is due to an immune cell-mediated inflammatory tumor microenvironment (TME) in these patients. However, a majority of CRC patients have an immune-suppressive TME, rendering ICB ineffective. As such, the long-term goal of this project is to understand and to modulate the T cell compartment to improve ICB responses in CRC patients that are typically non-responders to ICB therapy via non-coding RNAs. The objective of the proposal is to convert immune cell-depleted colon tumors into immune cell-enriched ones by manipulating T cell microRNA- 155 (miR-155), a classically proinflammatory microRNA (miRNA), and its targets. The central hypothesis is that T cell microRNA-155 promotes a Th1 and cytotoxic T lymphocyte (CTL)-enriched TME in colon cancer by inhibiting Th2 cell polarization and promoting ICB response. We also hypothesize that Ship1, a canonical miR- 155 target, promotes the proinflammatory TME by increasing IFNγ production fromTh1 cells and CTLs to reduce tumor growth. This hypothesis is based on preliminary data that correlate T cell gene signatures in human CRC with miR-155, which is necessary for antitumor immunity and ICB responses against colon cancer in our mouse models. The rationale for this work is that by altering T cell miRNAs or their downstreamtargets, we can promote inflammatory immune cell infiltration into the colon TME. Subsequently, an ICB response can be elicited in colon cancer patients regardless of MSI status. Based on our preliminary data, the central hypothesis will be tested through two specific aims: 1) determine whether T cell miR-155 inhibits Th2 cell polarization, promoting ICB responses in a mouse model of colon cancer, and 2) determine whether inhibiting SHIP-1, a T cell miR-155 target, promotes antitumor immunity, enhances ICB responses, and restricts tumor growth. This study is innovative as it aims to study MSI-H associated miR- 155 and SHIP-1 expression in the context of T cells, the primary target of ICB therapy. The proposed research is significant because it addresses the need for new therapeutic targets to potentiate ICB responses in non- responsive CRC patients.

项目总结/摘要 结直肠癌（CRC）是全球第二大致命癌症，发病率和死亡率居第三位 美国所有癌症的发病率。50岁以下的患者越来越多地出现晚期- 阶段CRC，其在当前护理标准下的五年存活率为14%。因此，新的治疗 正在探索免疫检查点阻断（ICB）等选择。T细胞失活通常发生在 肿瘤，导致免疫反应差。ICB通常通过阻断抗肿瘤免疫应答来诱导强烈的抗肿瘤免疫应答。 微卫星不稳定性高（MSI-H）转移性CRC患者的T细胞失活如此高的回复率 是由于这些患者中免疫细胞介导的炎症性肿瘤微环境（TME）。但 大多数CRC患者具有免疫抑制性TME，使得ICB无效。因此，长期 本项目的目标是了解和调节T细胞区室，以改善CRC的ICB反应 通常对通过非编码RNA进行的ICB治疗无反应的患者。建议的目的是 通过操纵T细胞microRNA将免疫细胞耗尽的结肠肿瘤转化为免疫细胞富集的肿瘤- 155（miR-155），一种经典的促炎性microRNA（miRNA）及其靶点。核心假设是， T细胞microRNA-155通过以下途径促进结肠癌中Th 1和细胞毒性T淋巴细胞（CTL）富集的TME 抑制Th 2细胞极化，促进ICB反应。我们还假设Ship 1，一个典型的miR- 155靶点，通过增加Th 1细胞和CTL产生IFNγ来促进促炎性TME， 肿瘤生长这一假设是基于初步数据，相关的T细胞基因签名在人类CRC 与miR-155，这是必要的抗肿瘤免疫和ICB反应对结肠癌在我们的小鼠 模型这项工作的基本原理是，通过改变T细胞miRNAs或其下游靶点，我们可以促进T细胞的增殖。 炎性免疫细胞浸润到结肠TME中。随后，可以在结肠中引起ICB反应， 无论MSI状态如何。 根据我们的初步数据，中心假设将通过两个具体目标进行测试：1）确定 T细胞miR-155是否抑制Th 2细胞极化，促进结肠癌小鼠模型中的ICB反应， 和2）确定抑制SHIP-1（一种T细胞miR-155靶标）是否促进抗肿瘤免疫， ICB反应，并限制肿瘤生长。这项研究是创新的，因为它的目的是研究MSI-H相关的miR- 155和SHIP-1在T细胞中的表达，ICB治疗的主要靶点。拟议研究 是重要的，因为它解决了对新的治疗靶点的需求，以加强非- 对CRC有反应的患者。