Chemerin in Tumor Immunity and Surveillance

描述（由申请方提供）：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，免疫刺激性树突状细胞和细胞毒性T细胞也参与肿瘤抑制。然而，免疫监视的效应细胞募集的生理机制仍然知之甚少。这个建议的基本假设是chemerin，最近描述的自然杀伤（NK）细胞和树突状细胞亚群的化学引诱物，伊萨免疫监视和肿瘤免疫的关键生理介质。这一假说是由以下观察结果提出的：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）中，chemerin在肿瘤发生期间在基因水平下调。我们的目标如下：一曰：确定肿瘤表达或瘤内chemerin是否抑制移植肿瘤的建立或生长，并确定chemerin受体CMKLR 1在chemerin介导的肿瘤抑制中的作用。将使用可移植肿瘤的良好建立的小鼠模型。通过比较用趋化素编码载体或对照载体转染的肿瘤细胞或瘤内注射趋化素的肿瘤的体内和体外生长，评价肿瘤表达的或相关的趋化素的作用。将使用CMKLR 1缺陷小鼠来定义CMKRL 1在观察到的肿瘤抑制中的作用。野生型肿瘤或静脉内“转移”模型的侧旁给药将评估局部肿瘤趋化蛋白表达诱导全身抗肿瘤免疫应答的能力。 2：定义由chemerin募集到肿瘤的细胞类型，以及它们参与chemerin抑制肿瘤生长。chemerin对包括NK细胞、树突状细胞（DC）和淋巴细胞在内的肿瘤浸润性白细胞（TIL）亚群的募集的作用将被证实。 通过比较从表达趋化蛋白的肿瘤与对照肿瘤分离的TIL来研究。为了确定它们参与chemerin介导的肿瘤生长抑制，将使用抗体和遗传方法耗尽募集的白细胞亚群。将使用CMKLR 1-/-小鼠评价CMKLR 1在TIL亚群募集中的作用。 3.检验内源性趋化蛋白介导自发性肿瘤发生过程中转化细胞的生理性免疫监视和抑制的假设。将在腺癌和黑色素瘤发展和转移的癌基因驱动模型中评价内源性CMKLR 1和趋化蛋白在肿瘤抑制中的作用。将在野生型、CMKLR 1-/-和趋化蛋白缺陷小鼠以及经工程改造具有免疫细胞特异性CMKRL 1缺陷的小鼠中比较肿瘤发展、进展和分化。 拟议的研究将定义chemerin在肿瘤发生的生理控制中的作用，并阐明相关的关键机制。这些结果可能会导致新的方法来参与癌症治疗的宿主免疫防御。

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.