Targeting PIM-2 Kinase for Improving Cancer Immunotherapy

靶向 PIM-2 激酶以改善癌症免疫治疗

基本信息

批准号：
10559633
负责人：
Xue-Zhong Yu
金额：
$ 52.8万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559633
关键词：
Acute T Cell Leukemia Adaptive Immune System Alloantigen Allogeneic Bone Marrow Transplantation Antigens Antitumor Response Breast Cancer Model CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cancer Patient Cell Cycle Progression Cell Survival Cells Data Development Dioxygenases Enzymes Epitopes Event FOXP3 gene Family member Genetic Hematology Human Immune Immune Evasion Immune Tolerance Immunity Immunosuppression Immunotherapy Implant Individual Investigation Knock-in Knock-out Knockout Mice Knowledge Lifting Malignant Neoplasms Mediating Metabolic Modeling Molecular Moloney Leukemia Virus Mus Mutant Strains Mice Myeloid-derived suppressor cells PD-1 blockade Pathway interactions Phosphorylation Phosphotransferases Play Protein Family Protein Isoforms Provirus Integration Publishing Regulation Regulatory T-Lymphocyte Research Role SILV gene Signal Transduction Source T cell response T-Cell Activation T-Cell Receptor Genes T-Lymphocyte Testing Time Tissues Transgenic Organisms Transplantation Tumor Antigens Tumor Immunity Tumor Promotion Work autoimmune pathogenesis cancer cell cancer immunotherapy cancer type chimeric antigen receptor chimeric antigen receptor T cells graft versus host disease induction immune checkpoint immune checkpoint blockade improved inhibitor integration site melanoma novel strategies overexpression pharmacologic prevent programmed cell death protein 1 proto-oncogene protein pim response restraint small hairpin RNA success therapeutic target translational approach tumor tumor growth tumor progression tumorigenesis

项目摘要

Abstract The adaptive immune system has the capacity to recognize and kill malignant cells. However, immune tolerant mechanisms that normally protect healthy tissues from autoimmune attack prevent the development of effective anti-tumor immunity. Tumor uses numerous immunosuppressive mechanisms to evade otherwise effective T-cell responses. A growing number of immune evasion mechanisms have been characterized including molecular and cellular mechanisms. Despite promising results achieved by targeting one or more of these immune evasion mechanisms, there is clearly room for improvement since only a subset of cancer patients usually respond to such a treatment. The PIM kinases have been studied extensively in tumorigenesis and as potential therapeutic targets for various cancers. PIM kinases are also expressed on activated T cells, but their roles in T-cell activity and function are inconclusive and the functions of each isoform in these cells remain unclear. Using genetically mutant mice, we found that individual PIM kinases play unique as well as overlapping roles in T-cell response to alloantigens. Strikingly, we consistently observed that PIM-2-deficient T cells had significantly increased ability to induce graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). More importantly, we found that CD8 T cells mount substantially strong anti- tumor responses when PIM-2 was deficient or blocked. Our preliminary studies have been extended from genetic to pharmacologic approaches and from mouse to human T cells. Thus, our preliminary studies provide compelling evidence that PIM-2 serves as a powerful negative regulator of T-cell immunity against cancer. Our Central Hypothesis is that targeting PIM-2 substantially promotes cancer immunotherapy while potentially inhibiting tumor progression directly. This hypothesis will be tested in the following two Specific Aims: 1) To delineate mechanistic action by which PIM-2 negatively regulates T-cell response; 2) To validate PIM-2 as an immunotherapy target against cancer. Based on our compelling preliminary data demonstrating for the first time that PIM-2 negatively regulates T-cell immunity, we expect to firmly validate this observation and to define the cellular and molecular mechanisms by which this regulation occurs. We also expect to demonstrate that blockade or inhibition of PIM-2 will enhance anti-tumor immunity against different types of cancer mediated by both mouse and human T cells.

抽象的适应性免疫系统具有识别和杀死恶性细胞的能力。然而，免疫耐受通常保护健康组织免受自身免疫攻击的机制可防止发展有效的抗肿瘤免疫力。肿瘤使用多种免疫抑制机制来逃避其他情况有效的 T 细胞反应。越来越多的免疫逃避机制已被表征包括分子和细胞机制。尽管通过针对一个或多个目标取得了有希望的结果这些免疫逃避机制，显然还有改进的空间，因为只有癌症的一个子集患者通常对这种治疗有反应。 PIM 激酶在肿瘤发生中已被广泛研究并作为各种癌症的潜在治疗靶点。 PIM 激酶也在活化的 T 细胞上表达，但它们在 T 细胞活性和功能中的作用尚无定论，并且这些细胞中每种亚型的功能仍不清楚。使用基因突变小鼠，我们发现单个 PIM 激酶发挥着独特的作用 T 细胞对同种抗原的反应中的重叠作用。引人注目的是，我们一致观察到 PIM-2 缺陷的 T 同种异体骨后细胞诱导移植物抗宿主病（GVHD）的能力显着增强骨髓移植（BMT）。更重要的是，我们发现 CD8 T 细胞具有很强的抗- PIM-2 缺乏或被阻断时的肿瘤反应。我们的初步研究已从从遗传学到药理学方法，从小鼠 T 细胞到人类 T 细胞。因此，我们的初步研究提供令人信服的证据表明，PIM-2 是 T 细胞抗癌免疫的强大负调节因子。我们的中心假设是，靶向 PIM-2 显着促进癌症免疫治疗，同时可能直接抑制肿瘤进展。该假设将在以下两个具体目标中得到检验：1）描述 PIM-2 负向调节 T 细胞反应的机制； 2) 验证 PIM-2 作为免疫疗法针对癌症。基于我们首次展示的令人信服的初步数据当 PIM-2 负向调节 T 细胞免疫时，我们期望坚定地验证这一观察结果并定义这种调节发生的细胞和分子机制。我们还希望证明阻断或抑制 PIM-2 将增强针对不同类型癌症介导的抗肿瘤免疫小鼠和人类 T 细胞。