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.

抽象的自适应免疫系统具有识别和杀死恶性细胞的能力。但是，免疫耐受通常保护健康组织免受自身免疫性攻击的机制阻止了有效的抗肿瘤免疫。肿瘤使用许多免疫抑制机制来逃避否则有效的T细胞响应。越来越多的免疫逃避机制被表征包括分子和细胞机制。尽管通过针对一个或多个实现了有希望的结果这些免疫逃避机制，显然有改善的余地，因为只有一部分癌症患者通常会对这种治疗做出反应。 PIM激酶已在肿瘤发生中进行了广泛的研究并作为各种癌症的潜在治疗靶标。 PIM激酶也在活化的T细胞上表达但是它们在T细胞活性和功能中的作用尚无定论，并且这些细胞中每个同工型的功能保持不清楚。使用遗传突变小鼠，我们发现单个PIM激酶发挥独特和在T细胞对同种抗原的响应中重叠的作用。令人惊讶的是，我们始终观察到PIM-2缺陷t 同种异体骨后，细胞具有显着提高的诱导移植物抗宿主病（GVHD）的能力骨髓移植（BMT）。更重要的是，我们发现CD8 T细胞具有很强的抗抗 PIM-2不足或阻塞时肿瘤反应。我们的初步研究已从遗传学到药理方法以及从小鼠到人T细胞。因此，我们的初步研究提供了令人信服的证据表明，PIM-2是针对癌症的T细胞免疫的强大负调节剂。我们的中心假设是靶向PIM-2基本上促进了癌症免疫疗法直接抑制肿瘤进展。该假设将在以下两个具体目的中进行检验：1） PIM-2通过负调节T细胞响应的划定机械作用； 2）验证PIM-2为免疫疗法靶向癌。基于我们引人入胜的初步数据，证明了第一个 PIM-2负调节T细胞免疫的时间，我们希望牢固验证这一观察结果并定义该调节发生的细胞和分子机制。我们也希望证明封锁或抑制PIM-2将增强抗肿瘤的免疫力，以针对由不同类型的癌症介导小鼠和人类T细胞。