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The Molecular and Cellular Basis of Cancer Immunoediting

癌症免疫编辑的分子和细胞基础

基本信息

批准号：
7215633
负责人：
ROBERT DAVID SCHREIBER
金额：
$ 40.42万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-21 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7215633
关键词：
Antigen Presentation Pathway Back Cell surface Cells Colon Complex Data Detection Development Down-Regulation Experimental Designs Galactosyltransferases Gene Expression Gene Silencing Gene Targeting Genes Genus Cola Glycolipids Goals Growth Guidelines Immune Immune system Immunity Immunocompetent Immunodeficient Mouse Immunologic Monitoring In Vitro Injection of therapeutic agent Knowledge Laboratories Ligands Link Lung Lymphocyte Malignant Neoplasms Mammary Neoplasms Messenger RNA Molecular Molecular Profiling Molecular Target Mus Neoplasm Transplantation Pathway interactions Phenotype Primary Neoplasm Process Production Proteins RNA Interference Research Research Infrastructure Resources Role Shapes Stress System Technology Testing Tumor-Derived Variant Wild Type Mouse Work base fibrosarcoma immunogenic immunogenicity in vivo insight neoplastic cell novel programs research study sarcoma tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): We have found that lymphocytes and IFNgamma function as an effective cancer immunosurveillance system to protect mice against development of spontaneous and chemically induced primary tumors. However, we also found that tumors arising in immunodeficient mice are more immunogenic than those from immunocompetent mice indicating that the immune system also selects for tumor variants that express reduced immunogenicity. These observations led us to refine the cancer immunosurveillance hypothesis into the "Cancer Immunoediting Hypothesis" that stresses the paradoxical host-protective and tumor sculpting effects of immunity on developing tumors. Whereas the Cancer Immunoediting hypothesis was formulated on the basis of functional criteria (different in vivo growth phenotypes of tumors from immunodeficient versus wild type mice), we now seek to define the process at the molecular level. Using gene-profiling approaches, we recently identified 180 genes that are differentially expressed in highly immunogenic, unedited sarcomas from immunodeficient mice versus edited sarcomas from wild type mice. CD1d represents one of these genes and its expression is selectively down regulated in edited sarcomas that form in the presence of an intact immune system. Injection of an unedited, highly immunogenic tumor (F535) that expresses high CD1d levels into partially immunodeficient mice leads to formation of escape variants that (a) display significantly reduced levels of CD1d mRNA and protein and (b) grow progressively when injected into unmanipulated wild type mice. Enforced expression of CD1d in F535 escape variants restores their high immunogenicity. Capitalizing on these novel observations, we will now define the molecular targets and underlying mechanisms of cancer immunoediting by pursuing the following four specific aims. In Specific Aim 1 we will determine whether CD1d is a generalized target of the cancer immunoediting process. In Specific Aim 2 we will identify and validate other genes that are additional targets of cancer immunoediting giving particular emphasis to our recent discovery that this process may additionally target the pathway leading to production of the glycolipid ligands of CD1d. In Specific Aim 3 we will define the mechanism(s) underlying the silencing of these genes. In Specific Aim 4 we will identify the pathway "editors" giving special emphasis to assessing a role for NKT cells in the editing process. This work will provide the first molecular and mechanistic insights into the cancer immunoediting process and may also establish molecular guidelines to judge the extent to which a tumor has been edited.

描述（由申请人提供）：我们发现淋巴细胞和IFNgamma作为一种有效的癌症免疫监视系统，可以保护小鼠免受自发和化学诱导的原发性肿瘤的发展。然而，我们也发现免疫缺陷小鼠产生的肿瘤比免疫正常小鼠产生的肿瘤更具免疫原性，这表明免疫系统也会选择表达免疫原性降低的肿瘤变异。这些观察结果使我们将癌症免疫监视假说完善为“癌症免疫编辑假说”，该假说强调免疫对肿瘤发展的矛盾的宿主保护和肿瘤雕刻作用。鉴于癌症免疫编辑假说是在功能标准（免疫缺陷小鼠与野生型小鼠体内肿瘤生长表型不同）的基础上制定的，我们现在寻求在分子水平上定义这一过程。使用基因谱分析方法，我们最近鉴定了180个基因，这些基因在免疫缺陷小鼠的高免疫原性、未编辑的肉瘤与野生型小鼠的编辑肉瘤中差异表达。CD1d代表其中一种基因，在免疫系统完整的情况下形成的编辑肉瘤中，其表达被选择性下调。将表达高CD1d水平的未经编辑的高免疫原性肿瘤（F535）注射到部分免疫缺陷小鼠中，导致形成逃逸变异体，这些变异体(a)显示CD1d mRNA和蛋白质水平显著降低，(b)注射到未操作的野生型小鼠时逐渐生长。在F535逃逸变异体中强制表达CD1d可恢复其高免疫原性。利用这些新的观察结果，我们现在将通过追求以下四个特定目标来定义癌症免疫编辑的分子靶点和潜在机制。在Specific Aim 1中，我们将确定CD1d是否是癌症免疫编辑过程的一般靶标。在Specific Aim 2中，我们将鉴定和验证其他基因，这些基因是癌症免疫编辑的额外靶标，特别强调我们最近的发现，该过程可能额外靶向导致CD1d糖脂配体产生的途径。在Specific Aim 3中，我们将定义这些基因沉默的机制。在Specific Aim 4中，我们将识别通路“编辑器”，特别强调评估NKT细胞在编辑过程中的作用。这项工作将为癌症免疫编辑过程提供第一个分子和机制方面的见解，也可能建立分子指南来判断肿瘤被编辑的程度。