Mechanism of IL-10 protective effect in development of childhood B cell acute lymphoblastic leukemia

IL-10对儿童B细胞急性淋巴细胞白血病发生发展的保护作用机制

• 批准号: 9767081
• 负责人: Briana Fitch
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767081
• 关键词: Acceleration; Address; Affect; Antigen Presentation; Autologous; Automobile Driving; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Biological; Biological Response Modifiers; Birth; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Child; Childhood Precursor B Lymphoblastic Leukemia; Chronic; DNA Damage; Data; Defect; Development; ETV6 gene; Frequencies; Future; Goals; Immune; Immune Evasion; Immune Targeting; Immune response; Immune system; Immunologic Surveillance; Immunologics; Immunosuppressive Agents; Incidence; Infection; Inflammation; Inflammatory; Interferons; Interleukin-10; Leukemic Cell; MHC Class I Genes; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Memory; Mus; Mutagenesis; Mutation; Newborn Infant; Nitrogen; Oxygen; Play; Population; Premalignant Cell; Prevention; Production; RUNX1 gene; Research; Risk; Role; SLEB2 gene; Solid; Solid Neoplasm; Somatic Mutation; Spleen; Stem cells; Stimulus; T memory cell; Testing; Therapeutic; Transplantation; Tumor Expansion; Tumor Immunity; Up-Regulation; Work; cytokine; cytotoxic; early childhood; epidemiology study; exhaust; expectation; experimental study; genetic regulatory protein; high risk; immune function; immunogenicity; immunological status; immunoregulation; insight; leukemia; leukemogenesis; lymph nodes; mouse model; neoplastic cell; neutrophil; progenitor; prognostic assays; prognostic value; protective effect; recruit; response; therapeutic target; transplant model; tumor

Project Summary Despite significant advances in understanding immune system abnormalities associated with B-ALL, how the status of the immune system at birth contributes to leukemia development is unknown. The distinguishing feature of this application is the cellular immunity perspective from which this question is addressed. I propose that in addition to B-cell progenitor intrinsic mutagenesis, non-B lineage immune cells also play a prominent role in B-ALL development. B-cell progenitors develop mutations as a direct response to inflammatory stimuli; however, the bone marrow contains other immune cell populations that can alter tumor development in response to inflammation. For example, in solid cancers, low levels of the cytokine IL-10 elicit strong pro-tumor responses of CD8 T cells and neutrophils. Specifically, CD8 T cells lose their ability to detect and lyse tumor cells, whereas neutrophils become elevated in frequency and increase the potential for reactive-oxygen and - nitrogen species (ROS/RNS) to induce cancer-associated mutations. I hypothesize that the anti-tumor mechanisms of IL-10 in increasing CD8 T cell activity and suppressing neutrophils are involved in the protective role of IL-10 in childhood B-ALL. In addition to developing B-ALL at an accelerated rate, Il10-/- TEL- AML1 Cdkn2a-/- mice have more exhausted, PD1+ CD8 memory T cells and are also characterized by higher levels of neutrophils than Il10+/+ TEL-AML1 Ckdn2a-/- mice. Experiments in Aim 1 will extend this observation by testing the impact of Il10 loss on the cytotoxic activity of CD8 memory T cells directed to leukemic B cells and on the ability of leukemic B cells to suppress their own immunogenicity, a mechanism of immune evasion. Additional experiments will also track the extent to which the recruitment of CD8 T cells to leukemias and their subsequent cytotoxic activity requires responsiveness to IL-10. These experiments will provide a biological demonstration for how CD8 T cells can be a factor in IL-10 mediated protection in B-ALL. Studies in Aim 2 will determine if the ROS/RNS produced by neutrophils of Il10-/- TEL-AML1 Cdkn2a-/- mice induce more DNA damage in B progenitors and contribute to decreased B-ALL latency compared to Il10+/+ TEL-AML1 Ckdn2a-/- mice. Activation and ROS/RNS production will be assessed in neutrophils isolated from the Il10-/- and Il10+/+ leukemias. I will then determine how Il10 loss impacts the mutational landscape of leukemia. The expectation is that the total number of mutations and ROS/RNS-associated mutational signatures will be increased in the leukemic B cells that developed in the absence of Il10. Finally, I will determine if the elevation of neutrophils that is characterized in pre-leukemic and leukemic Il10-/- TEL-AML1 Cdkn2a-/- mice is required for the acceleration of B-ALL development. The results of the proposed research will provide new biological insights into how immune defects at birth contribute to the development of childhood B-ALL. Moreover, this work has the potential to identify immune responses that can be targeted for leukemia prevention in children at high risk for B-ALL.

项目摘要 尽管在理解与B-All相关的免疫系统异常方面取得了重大进展，但如何 出生时免疫系统的状态导致白血病的发展尚不清楚。区别 该应用程序的特征是该问题的细胞免疫观点。我建议 除了B细胞祖细胞固有诱变外，非B谱系免疫细胞还发挥着突出的 在B-ALL开发中的作用。 B细胞祖细胞发展突变是对炎症刺激的直接反应。 但是，骨髓包含其他免疫细胞群，可以改变肿瘤的发展 对炎症的反应。例如，在固体癌症中，低水平的细胞因子IL-10会引起强肿瘤 CD8 T细胞和中性粒细胞的反应。具体而言，CD8 T细胞失去了检测和裂解肿瘤的能力 细胞，而中性粒细胞的频率升高，并增加了活性氧和 - 氮种（ROS/RN）诱导癌症相关的突变。我假设抗肿瘤 IL-10在增加CD8 T细胞活性和抑制嗜中性粒细胞中的机制参与 IL-10在儿童b-all中的保护作用。除了以加速速率开发b-all，iL10 - / - tel- AML1 CDKN2A - / - 小鼠筋疲力尽，PD1+ CD8存储T细胞，也具有更高的特征 中性粒细胞的水平比IL10+/+ Tel-AML1 CKDN2A - / - 小鼠。 AIM 1中的实验将扩展此观察结果 通过测试IL10损失对针对白血病B细胞的CD8记忆T细胞的细胞毒性活性的影响 以及白血病细胞抑制其自身免疫原性的能力，这是一种免疫逃避的机制。 其他实验还将跟踪CD8 T细胞募集到白血病及其的程度 随后的细胞毒性活性需要对IL-10的反应。这些实验将提供生物学 演示CD8 T细胞如何成为B-ALL中IL-10介导的保护的一个因素。 AIM 2的研究将 确定IL10 - / - Tel-AML1 CDKN2A - / - 小鼠产生的ROS/RN是否诱导更多DNA 与IL10+/+ tel-aml1 ckdn2a - / - 相比 老鼠。将在从IL10 - / - 和IL10+/+中分离的中性粒细胞中评估激活和ROS/RNS的产生 白血病。然后，我将确定IL10损失如何影响白血病的突变景观。期望 是，突变的总数和与ROS/RNS相关的突变特征将增加 在不存在IL10的情况下形成的白血病B细胞。最后，我将确定中性粒细胞的海拔 这在白血病学和白血病IL10 - / - tel-aml1 cdkn2a - / - 小鼠中的特征是 B-all开发的加速。拟议研究的结果将提供新的生物学见解 在出生时的免疫缺陷如何有助于儿童时期的发展。而且，这项工作有 鉴定可用于预防白血病的儿童高风险的免疫反应的潜力 对于B-all。