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Mechanisms of durable antitumor immunity via CD26hiCD4+ T cells

CD26hiCD4 T 细胞持久抗肿瘤免疫的机制

基本信息

批准号：
10227546
负责人：
Chrystal Mary Paulos
金额：
$ 36.86万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227546
关键词：
Address Adoptive Cell Transfers Adoptive Immunotherapy Antigens Autoimmune Process CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cell Differentiation process Cell physiology Cell surface Cells Clinic Clinical Data Dipeptidyl-Peptidase IV Engineering Engraftment Enzymes Exhibits Generations Goals Growth Human Human Activities Immune response Immunity Immunologic Memory Immunotherapy Impairment In Vitro Infusion procedures Interferon Type II Interleukin-17 Investigation Malignant Neoplasms Malignant neoplasm of pancreas Mediating Memory Mesothelioma Metabolism Modeling Mus Nature OX40 Pancreas Pathogenesis Pathway interactions Patients Pharmacologic Substance Phenotype Play Population Property Recurrence Regressing Melanoma Reporting Research Role Signaling Molecule T cell response T cell therapy T memory cell T-Lymphocyte TNFSF4 gene Testing Therapeutic Tumor Immunity base beta catenin cancer immunotherapy cancer therapy chimeric antigen receptor cytokine cytotoxic CD8 T cells cytotoxicity engineered T cells enzyme activity genetic manipulation improved in vivo insight interleukin-22 loss of function melanoma mesothelin overexpression pancreatic cancer cells pre-clinical preclinical study response self renewing cell self-renewal stem stem cells stemness tool tumor tumor eradication tumor necrosis factor ligand superfamily member 4

项目摘要

PROJECT SUMMARY Adoptive cell transfer (ACT) therapies for cancer patients have failed to fulfill their therapeutic promise, due to the transfer of short-lived and terminally differentiated cells. A lack of means for developing durable T cell potency has hampered ACT advancement in the clinic. Understanding and manipulating the pathways that sustain T cell memory will potentially unlock durable responses to tumors. We recent found that IL-17A/IFN- γ/IL-22-producing CD4+ T cells that express enzymatically active CD26 on their cell surface–termed human CD26hiCD4+ T cells–demonstrate exquisite responses to tumors compared to Th1, Th2 or Th17 cells. Further investigation revealed that these cells potently induce the expansion and engraftment of cytotoxic CD8+ T cells in vivo. Interestingly, we found that abrogating the enzymatic activity of CD26 on CD26hiCD4+ but not on CD8+ or CD26negCD4+ T cells with Alogliptin impaired their capacity to secrete IFN-γ. Collectively, our data suggest that CD26 plays a role in the cytotoxicity of CD26hiCD4+ T cells and could augment CD8+ T cell engraftment in vivo, in turn mediated curative responses in mice with murine and human tumors. The importance of CD26 on CD26hiCD4+ T cell function, metabolism and cytotoxicity will be investigated using various tools to pharmaceutically or genetically manipulate CD26 enzyme activity. Based on our new findings, the loss of function, metabolism and memory induced by the inhibition of CD26 enzymatic activity could potentially reduce the ability of CD26hiCD4+ T cells to support CD8+ T cells. It is important to deduce how CD26 on CD26hiCD4+ T cells cancer immunotherapy and if this activity and co-signaling molecules can be targeted for enhance therapy against this aggressive pancreatic cancer. We propose to gain further insight into CD26hiCD4+ T cell-mediated tumor immunity, hypothesizing that CD26 plays a crucial role in the anti-tumor activity of human CD26hiCD4+ T cells as well as their ability to support CD8+ T cells (Aim 1), and that these cells have unique self-renewing properties that prolong their efficacy of cancer immunotherapy after multiple rounds of serial transfer (Aim 2). We will also target co-stimulatory molecules on these cells to enhance their capacity to kill human pancreatic cancer (Aim 3). Our proposed research is expected to demonstrate that manipulation of the CD26 pathway may induce durable immunity against the growth and recurrence of advanced malignancies.

项目摘要用于癌症患者的连续性细胞转移（ACT）疗法由于以下原因而未能实现其治疗承诺：短寿命和终末分化细胞的转移。缺乏开发持久T细胞的方法效力阻碍了ACT在临床上的发展。理解和操纵持续T细胞记忆将潜在地开启对肿瘤的持久反应。我们最近发现IL-17 A/IFN-γ 在其细胞表面表达酶活性CD 26的产生γ/IL-22的CD 4 + T细胞-称为人T细胞与Th 1、Th 2或Th 17细胞相比，CD 26 hiCD 4 + T细胞对肿瘤表现出灵敏的应答。进一步研究显示，这些细胞有效地诱导细胞毒性CD 8 + T细胞的扩增和植入 in vivo.有趣的是，我们发现消除CD 26对CD 26 hiCD 4+而不是对CD 8+的酶活性，或CD 26 + CD 4 + T细胞与Aloglycan一起损害其分泌IFN-γ的能力。总的来说，我们的数据表明 CD 26在CD 26 hiCD 4 + T细胞的细胞毒性中起作用，并且可以增加CD 8 + T细胞在体内，反过来又介导了小鼠与鼠和人肿瘤的治疗反应。CD 26在将使用各种工具研究CD 26 hiCD 4 + T细胞功能、代谢和细胞毒性，药物或遗传上操纵CD 26酶活性。根据我们的新发现，通过抑制CD 26酶活性诱导的功能、代谢和记忆可能会降低 CD 26 hiCD 4 + T细胞支持CD 8 + T细胞的能力。因此，推测CD 26在CD 26 hiCD 4 + T细胞上的作用是非常重要的。细胞癌症免疫治疗，如果这种活性和共同信号分子可以靶向增强治疗对抗这种侵袭性胰腺癌我们建议进一步了解CD 26 hiCD 4 + T细胞介导的肿瘤免疫，假设CD 26在人CD 26 hiCD 4 + T细胞的抗肿瘤活性中起关键作用，细胞以及它们支持CD 8 + T细胞的能力（Aim 1），并且这些细胞具有独特的自我更新能力。在多轮连续转移后延长其癌症免疫治疗功效的特性（Aim 2）。我们还将靶向这些细胞上的共刺激分子，以增强它们杀死人类胰腺癌细胞的能力。癌症（目标3）。我们提出的研究有望证明，操纵CD 26途径，可以诱导针对晚期恶性肿瘤的生长和复发的持久免疫力。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Basics of Artificial Antigen Presenting Cells in T Cell-Based Cancer Immunotherapies.

基于 T 细胞的癌症免疫疗法中人工抗原呈递细胞的基础知识。

DOI：
发表时间：
2017
期刊：
Journal of immunology research and therapy
影响因子：
0
作者：
Neal,LillianR;Bailey,StefanieR;Wyatt,MeganM;Bowers,JacobS;Majchrzak,Kinga;Nelson,MichelleH;Haupt,Carl;Paulos,ChrystalM;Varela,JuanC
通讯作者：
Varela,JuanC