Targeting PIM-2 Kinase for Improving Cancer Immunotherapy

靶向 PIM-2 激酶以改善癌症免疫治疗

• 批准号: 10364948
• 负责人: Xue-Zhong Yu
• 金额: $ 55.29万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 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/10364948
• 关键词: Acute T Cell Leukemia; Adaptive Immune System; Alloantigen; Allogeneic Bone Marrow Transplantation; Antigens; Antitumor Response; Breast Cancer Model; CD4 Positive T Lymphocytes; 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; Pharmacology; Phosphorylation; Phosphotransferases; Play; Protein Family; Protein Isoforms; Provirus Integration; Publishing; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Source; T cell response; T-Lymphocyte; Testing; Time; Tissues; Transgenic Organisms; Transplantation; Tumor Antigens; Tumor Immunity; Work; autoimmune pathogenesis; base; cancer cell; cancer immunotherapy; cancer type; chimeric antigen receptor; chimeric antigen receptor T cells; gp100 Antigen; graft vs host disease; immune checkpoint; immune checkpoint blockade; improved; inhibitor; integration site; melanoma; novel strategies; overexpression; prevent; programmed cell death protein 1; proto-oncogene protein pim; response; small hairpin RNA; success; therapeutic target; translational approach; tumor; tumor growth; tumor progression; tumorigenesis

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.

摘要 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 正常情况下保护健康组织免受自身免疫攻击的机制阻止了 有效的抗肿瘤免疫。肿瘤使用多种免疫抑制机制来逃避 有效的T细胞反应。越来越多的免疫逃避机制已经被描述出来 包括分子和细胞机制。尽管通过将一个或多个 这些免疫逃避机制，显然有改进的空间，因为只有一小部分癌症 患者通常对这种治疗有反应。PIM激酶在肿瘤发生中有广泛的研究。 并作为各种癌症的潜在治疗靶点。PIM激酶也表达在激活的T细胞上， 但它们在T细胞活动和功能中的作用尚不确定，这些细胞中每种异构体的功能 目前仍不清楚。使用基因突变的小鼠，我们发现单个PIM激酶发挥着独特的作用 T细胞对同种异体抗原反应的重叠作用。值得注意的是，我们一直观察到PIM-2缺陷的T细胞 同种异体骨移植后细胞诱导移植物抗宿主病(GVHD)的能力显著增强 骨髓移植(BMT)。更重要的是，我们发现CD8T细胞可以很强地抵抗 当PIM-2缺乏或被阻断时，肿瘤反应。我们的初步研究已从 从遗传学到药理学的途径，以及从小鼠到人类的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是对抗癌症的T细胞免疫的强大负面调节因子。我们的 中心假设是靶向PIM-2实质上促进了癌症免疫治疗，同时潜在地 直接抑制肿瘤进展。这一假设将在以下两个具体目标中得到检验：1) 描述PIM-2负性调节T细胞反应的机制；2)验证PIM-2作为一种 针对癌症的免疫治疗。基于我们首次展示的令人信服的初步数据 PIM-2负性调节T细胞免疫的时间，我们希望坚定地验证这一观察结果，并确定 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将增强对不同类型癌症的抗肿瘤免疫 小鼠和人类的T细胞。