Chemerin in Tumor Immunity and Surveillance

描述（由申请人提供）：肿瘤发生受免疫监视机制控制。自然杀伤细胞是天然抗肿瘤免疫的重要介质，免疫刺激树突状细胞和细胞毒性T细胞也参与肿瘤抑制。然而，免疫监视效应细胞募集的生理机制仍然知之甚少。这一提议的基本假设是，趋化素是一种最近被描述的自然杀伤细胞（NK）和树突状细胞亚群的趋化剂，是免疫监视和肿瘤免疫的关键生理介质。在动物模型和许多人类实体组织肿瘤（包括黑色素瘤和前列腺癌）的肿瘤发生过程中，趋化素在基因水平上下调，这一观察结果提出了这一假设。我们的目的如下：1 .确定肿瘤表达的或肿瘤内的趋化素是否抑制移植肿瘤的建立或生长，并确定趋化素受体CMKLR1在趋化素介导的肿瘤抑制中的作用。将使用成熟的可移植肿瘤小鼠模型。肿瘤表达的或相关的趋化素的作用将通过比较体内和体外的肿瘤细胞的生长来评估，这些肿瘤细胞转染了趋化素编码载体或对照载体，或肿瘤内注射了趋化素。cmklr1缺陷小鼠将用于确定CMKRL1在观察到的肿瘤抑制中的作用。对侧给药野生型肿瘤或静脉注射“转移”模型将评估局部肿瘤趋化素表达诱导全身抗肿瘤免疫反应的能力。2：定义被趋化素募集到肿瘤的细胞类型，以及它们在趋化素抑制肿瘤生长中的作用。趋化素对肿瘤浸润性白细胞（TIL）亚群（包括NK细胞、树突状细胞（DC）和淋巴细胞）募集的影响将进一步深入研究

DESCRIPTION (provided by applicant): Tumorigenesis is controlled by mechanisms of immune surveillance. Natural killer cells are important mediators of innate anti-tumor immunity, and immunostimulatory dendritic cells and cytotoxic T cells participate in tumor suppression as well. However, physiologic mechanisms of effector cell recruitment for immune surveillance remain poorly understood. The underlying hypothesis of this proposal is that chemerin, a recently described chemoattractant for natural killer (NK) cells and subsets of dendritic cells, isa key physiological mediator of immune surveillance and of tumor immunity. This hypothesis is suggested by the observation that chemerin is downregulated at the gene level during tumorigenesis in animal models and in many human solid tissue neoplasms, including melanoma and prostate cancer. Our Aims are as follows: 1: Determine whether tumor-expressed or intratumoral chemerin inhibits the establishment or growth of transplanted tumors, and define the role of the chemerin receptor CMKLR1 in chemerin-mediated tumor suppression. Well-established mouse models of transplantable tumors will be used. The effects of tumor- expressed or associated chemerin will be evaluated by comparing the in vivo and in vitro growth of tumor cells transfected with chemerin-encoding or control vectors, or of tumors injected with chemerin intratumorally. CMKLR1-deficient mice will be used to define the CMKRL1 in observed tumor suppression. Contralateral administration of wild type tumors or intravenous "metastasis" models will assess the ability of local tumor chemerin expression to induce systemic anti-tumor immune responses. 2: Define cell types recruited to tumors by chemerin, and their involvement in chemerin suppression of tumor growth. The effects of chemerin on recruitment of tumor infiltrating leukocyte (TIL) subsets including NK cells, dendritic cells (DC), and lymphocytes will be studied by comparing TIL isolated from chemerin-expressing vs control tumors. To define their involvement in chemerin-mediated tumor growth inhibition, recruited leukocyte subsets will be depleted using antibody and genetic approaches. The role of CMKLR1 in recruitment of TIL subsets will be evaluated using CMKLR1-/- mice. 3. Test the hypothesis that endogenous chemerin mediates physiologic immune surveillance and inhibition of transformed cells during spontaneous tumorigenesis. The role of endogenous CMKLR1 and chemerin in tumor suppression will be evaluated in oncogene driven models of adenocarcinoma and melanoma development and metastasis. Tumor development, progression and differentiation will be compared in wild type, CMKLR1-/- and chemerin-deficient mice, and in mice engineered to have immune-cell specific CMKRL1 deficiency. The proposed studies will define the role of chemerin in the physiologic control of tumorigenesis, and will elucidate key mechanisms involved. The results may lead to novel approaches to engage host immune defenses for cancer therapy.