A Novel Clinical Challenge in Brain Tumor Immunology: T cell Sequestration

脑肿瘤免疫学的新临床挑战：T 细胞隔离

• 批准号: 10055775
• 负责人: Peter Fecci
• 金额: $ 33.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055775
• 关键词: Acquired Immunodeficiency Syndrome; Back; Blood; Bone Marrow; Brain; Brain Neoplasms; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Count; Cell surface; Clinical; Contracts; Data; Down-Regulation; Environment; Exhibits; Functional disorder; Glioblastoma; Goals; Hour; Immune; Immunity; Immunotherapeutic agent; Immunotherapy; Implant; Lymphopenia; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Marrow; Mediating; Mediator of activation protein; Methods; Monitor; Mus; Patients; Peripheral; Pharmacology; Population Control; Primary Brain Neoplasms; Production; Role; Serum; Site; Sphingosine-1-Phosphate Receptor; Spleen; T cell therapy; T-Cell Homing Receptors; T-Lymphocyte; TNF gene; Testing; Therapeutic; Thymus Gland; Transgenic Mice; Wild Type Mouse; base; improved; ipilimumab; lymph nodes; lymphoid organ; mouse model; novel; overexpression; receptor; response; sphingosine 1-phosphate; subcutaneous; success; tumor; tumor immunology; tumor microenvironment

ABSTRACT Glioblastoma (GBM), the most common primary malignant brain tumor, is among the most lethal of cancers. It is also among the most immunosuppressive, impeding the success of immune-based therapies. The tumor has an especially devastating impact on T cells, which either vanish from the blood and lymphoid organs or persist in a state of pronounced dysfunction. While T cell dysfunction has been well characterized, their disappearance has not, instead remaining a mystery for decades. Our novel data reveal that the missing T cells are frequently found in large numbers in the bone marrow. This proves true in both patients and mice with GBM, each of which harbor a 3 to 5-fold expansion in bone marrow T cell counts. Such expansion contrasts starkly with observations of AIDS-level CD4 T cell counts in blood and gross contraction of other lymphoid organs, including the spleen. Sequestration in bone marrow is suggested as T cells transferred into GBM- bearing mice accumulate in the marrow disproportionately over the ensuing 24 hours. Furthermore, when marrow-sequestered T cells from GBM-bearing mice are transferred back into controls, they preferentially re- accumulate in the bone marrow, suggesting T cells acquire alterations eliciting their sequestration. Notably, these phenomena are observed when other cancers are implanted intracranially, but never when the same tumors are placed subcutaneously, including GBM. This implies a unique role for the brain environment in mediating the T cell sequestration. Our preliminary studies suggest that T cells become sequestered in bone marrow in the GBM-bearing state as a result of diminished levels of T cell surface sphingosine-1-phosphate receptor 1 (S1P1). We propose to: 1) further define the role of S1P1 in mediating bone marrow T cell sequestration in GBM; 2) delineate the upstream determinants of S1P1 downregulation in the tumor-bearing state; and 3) devise means of reversing T cell sequestration, with the ultimate goals of replenishing the missing peripheral T cell pool and improving the efficacy of immune-based GBM therapies.

抽象的 胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，是最致命的癌症之一。它 也是最免疫抑制作用之一，阻碍了免疫疗法的成功。肿瘤有 对T细胞的特别破坏性影响，T细胞从血液和淋巴器官中消失或持续存在 在明显的功能障碍状态下。虽然T细胞功能障碍的表征已经很好 失踪没有，而是几十年来一直是一个谜。我们的新数据表明，缺失的t 细胞经常在骨髓中大量发现。这在患者和小鼠中都证明是正确的 GBM，每个GBM在骨髓T细胞计数中都有3至5倍的扩张。这种扩展对比 鲜明地观察到血液中的艾滋病级CD4 T细胞计数和其他淋巴管的总体收缩 器官，包括脾脏。提出骨髓中的固隔，因为T细胞转移到GBM- 在随后的24小时内，轴承小鼠在骨髓中积聚了不成比例。此外，什么时候 将来自GBM的小鼠的骨髓遗留的T细胞转移到对照中，优先重新 积聚在骨髓中，表明T细胞获得了引起其隔离的变化。尤其， 当其他癌症内颅内植入时，会观察到这些现象 皮下放置肿瘤，包括GBM。这意味着在大脑环境中起着独特的作用 介导T细胞隔离。我们的初步研究表明，T细胞在骨骼中隔离 由于T细胞表面鞘氨酸-1-磷酸的水平降低，含GBM的骨髓在含GBM状态下 受体1（S1P1）。我们建议：1）进一步定义S1P1在介导骨髓T细胞中的作用 GBM中的隔离； 2）描述肿瘤肿瘤下调的上游决定因素 状态; 3）设计逆转T细胞隔离的手段，其最终目标是补充缺失 周围T细胞池并提高了基于免疫的GBM疗法的功效。

项目成果

T-cell Dysfunction in Glioblastoma: Applying a New Framework.

• DOI: 10.1158/1078-0432.ccr-18-0047
• 发表时间: 2018-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Woroniecka KI;Rhodin KE;Chongsathidkiet P;Keith KA;Fecci PE
• 通讯作者: Fecci PE