权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要