Blocking an Endogenous Inhibitor of Anti-tumor Leukocyte Recruitment

阻断抗肿瘤白细胞募集的内源性抑制剂

基本信息

批准号：
9404565
负责人：
Kevin Brulois
金额：
$ 0.06万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9404565
关键词：
Address Adenocarcinoma Adverse effects Antibodies Antigens Avastin Binding Blocking Antibodies Bone Marrow Bone Marrow Cells Breast Carcinoma CMKLR1 gene CTLA4 gene Cancerous Cells Chemotactic Factors Clinical Complement Data Exclusion Female Flow Cytometry GPER gene Goals Immune Immune Evasion Immune system Immunization Immunohistochemistry Immunologic Adjuvants Immunosuppressive Agents Immunotherapy Injectable Interferon-alpha Interleukin-2 Knockout Mice Lead Leukocytes Measurement Mediating Methods Modeling Mus Natural Killer Cells Patients Phenotype Process Recruitment Activity Research Role Stromal Cells T-Cell Activation Testing Therapeutic Therapeutic Intervention Tissues Treatment Efficacy Tumor Immunity Tumor Promotion Tumor Suppression Tumor Tissue Y 90 Ibritumomab Tiuxetan antitumor effect base beta-Chemokines cancer cell cancer immunotherapy clinical application clinical efficacy in vivo inhibitor/antagonist insight macrophage melanoma neoplastic cell pre-clinical prevent public health relevance receptor reconstitution success trafficking tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): A major immune evasion strategy of tumor cells is the establishment of an immunosuppressive tumor microenvironment through the selective recruitment of pro-tumor immune cells and the exclusion of anti-tumor immune cells. However, the underlying cell trafficking mechanisms that govern this process are incompletely understood. Chemerin is a chemoattractant that, when expressed or presented in tumors, selectively recruits CMKLR1+ anti-tumor leukocytes in tumor tissues, resulting in decreased tumor growth rates. Our preliminary data show that B16 melanoma tumor growth is reduced in mice lacking the atypical (non-signaling) chemerin receptor CCRL2. I hypothesize that 1) CCRL2, by binding and sequestering chemerin away from tumor tissue, inhibits chemerin-dependent leukocyte recruitment into B16 tumor tissue and 2) therapeutic intervention with CCRL2-blocking antibodies should recapitulate CCRL2-deficiency and unleash chemerin-dependent anti-tumor immunity. In Aim 1, the anti-tumor effects of CCRL2 deficiency will be evaluated in two in vivo tumorigenesis models: B16 melanoma and JC adenocarcinoma. Aim 2 is to define the in vivo mechanisms of CCRL2- dependent enhancement of tumor growth. Specifically, I will determine whether CCRL2 on stromal or hematolymphoid cells is necessary or sufficient to facilitate tumor growth. Moreover, I will test the hypothesis that CCRL2 facilitates tumor growth by sequestering chemerin, preventing the attractant from reaching or establishing a functional attractant gradient within tumor tissues. In Aim 3, I will evaluate the pre-clinical efficacy of antibody-mediated blockade of CCRL2 using in vivo tumor growth models. I will use the established B16 melanoma model and/or JC adenocarcinoma models to assess in vivo tumor growth. In order to address the mechanistic role of hematolymphoid versus stromal cells in the CCRL2 effect, bone marrow (BM) chimeric mice will be generated by reconstituting irradiated wild type or CCRL2 KO mice with wild type or CCRL2 KO bone marrow cells. To assess whether the effect of CCRL2 deficiency on tumor growth is dependent on chemerin-mediated recruitment of CMKLR1pos cells, double KO mice (CCRL2/chemerin-double KO and CCRL2/CMKLR1 double KO) will be compared to single KO mice for their ability to support tumor growth. Finally, I will evaluate the therapeutic efficacy of antagonistic antibodies against CCRL2 using in vivo tumor models. By targeting an endogenous host-cell expressed antigen to block inhibition of anti-tumor cell recruitment, anti-CCRL2 therapy will likely synergize with or at least complement existing cancer immunotherapies, which target mechanisms of activation of hematolymphoid cells. The proposed research will provide crucial mechanistic insights and proof-of-concept data for the potential clinical applications of anti- CCRL2 therapy.

描述（由适用提供）：主要的免疫抑制肿瘤细胞是通过选择性募集促肿瘤免疫细胞的选择性募集，并排除抗肿瘤免疫细胞，建立了免疫抑制性肿瘤微环境。但是，尚未完全理解控制这一过程的基本细胞运输机制。 Chemerin是一种化学吸收剂，在肿瘤中表达或表现出来，在肿瘤组织中有选择地募集CMKLR1+抗肿瘤白细胞，从而导致肿瘤生长率降低。我们的初步数据表明，缺乏非典型（非信号）化学蛋白受体CCRL2的小鼠中B16黑色素瘤肿瘤的生长降低。我假设1）CCRL2，通过结合和隔离化学素从肿瘤组织中脱离化学蛋白，可以抑制化学依赖性的白细胞募集到B16肿瘤组织中，而2）用CCRL2-Block-Block-Block-Block-Block-blocking抗体进行治疗性干预，应将CCRL2缺乏症状和抗抑制剂抑制性依赖性抗体依赖性依赖性抗体依赖性。在AIM 1中，将在两个体内肿瘤发生模型中评估CCRL2缺乏症的抗肿瘤作用：B16黑色素瘤和JC腺癌。目的2是定义CCRL2依赖性增强肿瘤生长的体内机制。具体而言，我将确定在基质或血淋巴样细胞上的CCRL2是否需要或足以促进肿瘤生长。此外，我将检验以下假设：CCRL2通过隔离化学蛋白来促进肿瘤的生长，从而阻止吸引力到达或建立肿瘤组织中的功能吸引力梯度。在AIM 3中，我将使用体内肿瘤生长模型评估CCRL2抗体介导的CCRL2封闭的临床前效率。我将使用已建立的B16黑色素瘤模型和/或JC腺癌模型来评估体内肿瘤生长。为了解决CCRL2效应中血压相对于基质细胞与基质细胞的机械作用，通过将辐照的野生型或CCRL2 KO小鼠用野生型或CCRL2 KO骨髓细胞重新建立，将产生骨髓（BM）嵌合小鼠。为了评估CCRL2缺乏对肿瘤生长的影响是否取决于化学介导的CMKLR1POS细胞的募集，双KO小鼠（CCRL2/Chemerin-double KO和CCRL2/CMKLR1双KO）将与单个KO小鼠相比支持肿瘤的生长。最后，我将使用体内肿瘤模型评估针对CCRL2的拮抗抗体的治疗效率。通过靶向内源性宿主细胞表达抗原以阻断抗肿瘤细胞募集的抑制作用，抗CCRL2治疗可能会与现有的癌症免疫疗法协同或至少补充，该癌症的靶向造成血瘤细胞的激活机制。拟议的研究将为抗CCRL2治疗的潜在临床应用提供至关重要的机械见解和概念验证数据。