Memory potential, molecular characterization, and translational applications of the novel ThEO/TcEO T cell phenotype

新型 ThEO/TcEO T 细胞表型的记忆潜力、分子表征和转化应用

• 批准号: 9229761
• 负责人: Todd Bartkowiak
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229761
• 关键词: Accounting; Address; Adoptive Transfer; Agonist; Antibodies; Antigens; Basic Science; Biological Markers; Boxing; CD8B1 gene; Cancer Immunology Science; Cell Therapy; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Communities; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Diagnostic Neoplasm Staging; Disease; Disseminated Malignant Neoplasm; Education; Ensure; Flow Cytometry; Future; Goals; Human; Immune; Immune response; Immunobiology; Immunologic Memory; Immunologist; Immunotherapy; Knowledge; Longevity; Maintenance; Mediating; Memory; Mentors; Mentorship; Methods; Microarray Analysis; Modality; Modeling; Molecular; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Phenotype; Positioning Attribute; Process; Research; Research Personnel; Research Project Grants; Science; Scientist; Skin Cancer; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Tissues; Toxic effect; Training; Tumor Immunity; Validation; Work; Writing; base; cancer immunotherapy; career; clinical phenotype; cytotoxic; cytotoxicity; doctoral student; experience; human disease; immunoregulation; insight; liver inflammation; long term memory; melanoma; neoplasm immunotherapy; novel; pre-clinical; pre-doctoral; programs; receptor; response; response biomarker; success; transcription factor; treatment response; trend; tumor; tumor immunology

Melanoma is an aggressive form of skin cancer that accounts for the majority of skin cancer related deaths. Newly developed therapeutic modalities, however, have offered hope in treating this once incurable disease. Advances in immunotherapy, particularly the approval of anti-CTLA-4 and anti-PD-1 therapy for melanoma and non-small-cell lung cancer have demonstrated the potential of immune modulation in not only treating, but curing metastatic cancers. The clinical success of these checkpoint blockade antibodies has expanded the potential of targeting other T cell co-receptor targets to potentiate robust anti-tumor immune responses that may afford greater clinical benefit. Use of agonist antibodies directed towards 4-1BB, a co-stimulatory receptor expressed on activated T cells, has proven effective in treating multiple tumor types in both murine systems and early human clinical trials. The exquisite potency of α4-1BB therapy in boosting anti-tumor immunity is due, in part, to 4-1BB-mediated programming of T cells to assume a highly cytotoxic phenotype driven by the T box transcription factor Eomesodermin (Eomes) and characterized by expression of the co-inhibitory receptor KLRG1. These Eomes+KLRG1+ CD8 (TcEO) and CD4 (ThEO) T cells mediate potent anti-tumor responses capable of complete tumor rejection. We hypothesize that this Eomes-driven ThEO/TcEO T cell phenotype represents a novel molecular program which forms stable immunologic memory despite maintenance of highly cytotoxic effector function and KLRG1 expression. By characterizing the unique pathways downstream of 4-1BB activation which create the ThEO program, we will establish the molecular basis for the exquisite cytotoxicity of these cells, as well as their paradigm-breaking capacity to express KLRG1 yet retain proliferative capacity and memory potential. Investigating the detailed memory phenotype of these cells, as well as their replicative capacity and longevity following antigenic rechallenge will deepen our understanding of 4-1BB agonist antibody immunobiology and provide insight into their translational value in a cell therapy setting. Finally, exploring the importance of ThEO phenotype T cells for mediating both the beneficial anti-tumor efficacy as well as the detrimental liver inflammation associated with 4-1BB agonist antibody will provide mechanistic insights as well as potential guiding biomarkers for future clinical studies. The proposed research project will provide extensive technical training in both basic and clinical research, scientific writing, collaboration, and lab management necessary to pursue a career as an independent investigator.

黑色素瘤是一种侵袭性皮肤癌，占皮肤癌相关死亡的大部分。 然而，新开发的治疗方式为治疗这种曾经无法治愈的疾病带来了希望。 免疫疗法的进展，特别是抗 CTLA-4 和抗 PD-1 疗法批准用于黑色素瘤和 非小细胞肺癌已证明免疫调节的潜力不仅可以治疗，而且可以 治愈转移性癌症。这些检查点阻断抗体的临床成功扩大了 靶向其他 T 细胞辅助受体靶标以增强强大的抗肿瘤免疫反应的潜力 可能会带来更大的临床益处。使用针对 4-1BB（共刺激受体）的激动剂抗体 在活化的 T 细胞上表达，已被证明可有效治疗小鼠系统中的多种肿瘤类型 和早期人体临床试验。 α4-1BB疗法在增强抗肿瘤免疫力方面的卓越功效是 部分归因于 4-1BB 介导的 T 细胞编程，呈现出由 T 驱动的高细胞毒性表型 盒转录因子 Eomesodermin (Eomes)，其特征在于共抑制受体的表达 KLRG1。这些 Eomes+KLRG1+ CD8 (TcEO) 和 CD4 (ThEO) T 细胞介导有效的抗肿瘤反应 能够完全排斥肿瘤。我们假设这种 Eomes 驱动的 ThEO/TcEO T 细胞 表型代表了一种新的分子程序，尽管它形成了稳定的免疫记忆 维持高细胞毒性效应子功能和 KLRG1 表达。通过描绘独特的 创建 ThEO 程序的 4-1BB 激活下游途径，我们将建立分子 这些细胞的精致细胞毒性及其打破范式的表达能力的基础 KLRG1 仍保留增殖能力和记忆潜力。研究详细的记忆表型 这些细胞，以及它们在抗原再攻击后的复制能力和寿命，将加深我们对 了解 4-1BB 激动剂抗体免疫生物学并深入了解其在 细胞治疗设置。最后，探讨 ThEO 表型 T 细胞对于介导 有益的抗肿瘤功效以及与 4-1BB 激动剂相关的有害肝脏炎症 抗体将为未来的临床研究提供机制见解以及潜在的指导生物标志物。这 拟议的研究项目将提供基础和临床研究、科学 写作、协作和实验室管理是追求独立研究者职业所必需的。