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: 9401990
• 负责人: Briana Fitch
• 金额: $ 3.57万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401990
• 关键词: Acceleration; Acute Lymphocytic Leukemia; Address; Affect; Antigen Presentation; Autologous; Automobile Driving; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Biological; Biological Response Modifiers; Birth; Blast Cell; 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; Interferon-alpha; Interleukin-10; Leukemic Cell; MHC Class I Genes; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; Mutagenesis; Mutation; Newborn Infant; Nitrogen; Oxygen; Play; Population; Premalignant Cell; Prevention; Production; RUNX1 gene; Recruitment Activity; Research; Risk; Role; 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; response; therapeutic target; 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， 出生时免疫系统的状态对白血病发展的贡献是未知的。述区分 本申请的特征是从细胞免疫的角度来解决这个问题。我提议 除了B细胞祖细胞内在诱变之外，非B谱系免疫细胞也在免疫系统中起着突出的作用。 在B-ALL发展中的作用。B细胞祖细胞发生突变作为对炎症刺激的直接反应; 然而，骨髓含有其他免疫细胞群，可以改变肿瘤的发展， 炎症反应。例如，在实体癌中，低水平的细胞因子IL-10引起强烈的促肿瘤生长， CD 8 T细胞和中性粒细胞的反应。具体地说，CD 8 T细胞失去了检测和裂解肿瘤的能力， 细胞，而中性粒细胞变得频率升高，并增加活性氧和- 氮物种（ROS/RNS）诱导癌症相关突变。我假设抗肿瘤药物 IL-10增加CD 8 T细胞活性和抑制中性粒细胞的机制参与了 IL-10在儿童B-ALL中的保护作用除了以加速的速度发展B-ALL外，Il 10-/- TEL- AML 1 Cdkn 2a-/-小鼠具有更多耗尽的PD 1 + CD 8记忆T细胞，并且其特征还在于更高的CD 8 + T细胞。 IL 10 +/+ TEL-AML 1 Ckdn 2a-/-小鼠的中性粒细胞水平。目标1中的实验将扩展这一观察结果 通过测试IL 10缺失对针对白血病B细胞的CD 8记忆T细胞的细胞毒活性的影响 以及白血病B细胞抑制自身免疫原性的能力，免疫逃避机制。 另外的实验也将跟踪CD 8 T细胞向白血病的募集程度及其对白血病的影响。 随后的细胞毒活性需要对IL-10的应答性。这些实验将提供一种生物学 证明了CD 8 T细胞如何成为IL-10介导的B-ALL保护作用的一个因素。目标2中的研究将 确定IL 10-/-TEL-AML 1 Cdkn 2a-/-小鼠的中性粒细胞产生的ROS/RNS是否诱导更多的DNA 与IL 10 +/+ TEL-AML 1 Ckdn 2a-/-相比，B祖细胞损伤并导致B-ALL潜伏期降低 小鼠将在从Il 10-/-和Il 10 +/+分离的中性粒细胞中评估活化和ROS/RNS产生。 白血病然后，我将确定IL 10的丢失如何影响白血病的突变景观。的预期 突变总数和ROS/RNS相关的突变特征将在 白血病B细胞在缺乏IL 10的情况下发展。最后，我将确定中性粒细胞的升高 在白血病前和白血病II 10-/-TEL-AML 1 Cdkn 2a-/-小鼠中表征的CDKN 2a是 加速B-ALL的发展。拟议研究的结果将提供新的生物学见解 出生时的免疫缺陷如何导致儿童B-ALL的发展。此外，这项工作 确定可用于高危儿童白血病预防的免疫反应的潜力 对于B-ALL。