The Molecular and Cellular Basis of Cancer Immunoediting

癌症免疫编辑的分子和细胞基础

• 批准号: 6771282
• 负责人: ROBERT DAVID SCHREIBER
• 金额: $ 39.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-21 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6771282
• 关键词: CD1 molecule; RNA interference; T lymphocyte; flow cytometry; galactosyltransferases; gene expression; gene induction /repression; genetically modified animals; glycolipids; immunogenetics; laboratory mouse; ligands; natural killer cells; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplastic cell; neoplastic growth; polymerase chain reaction

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充当有效的癌症免疫监视系统，可保护小鼠免受自发和化学诱导的原发性肿瘤的发展。但是，我们还发现，在免疫缺陷小鼠中产生的肿瘤比免疫能力小鼠的肿瘤更具免疫原性，表明免疫系统还选择表达降低免疫原性的肿瘤变异体。这些观察结果使我们将癌症免疫监测假说改进到“癌症免疫编辑假设”中，该假设强调了免疫对肿瘤的矛盾宿主保护和肿瘤雕塑作用。虽然根据功能标准（来自免疫缺陷型肿瘤的体内生长表型与野生型小鼠与野生型小鼠的体内生长表型不同），但我们试图在分子水平上定义该过程。使用基因促进方法，我们最近确定了180个基因，这些基因在来自免疫缺陷小鼠的高度免疫原性的未编辑的肉瘤中差异表达，而不是野生型小鼠的肉瘤编辑的肉瘤。 CD1D代表了这些基因之一，其表达在完整的免疫系统存在下形成的编辑肉瘤中被选择性地下调。注射未经编辑的高度免疫原性肿瘤（F535），该肿瘤表达高CD1D水平高于部分免疫缺陷小鼠，导致逃生变体的形成（a）（a）在未经操纵的野生型野生型小鼠中时（a）显示出（a）显着降低CD1D mRNA和蛋白质和（B）的水平。 F535中CD1D的表达恢复了其高免疫原性。利用这些新颖的观察结果，我们现在将通过追求以下四个特定目标来定义癌症免疫程序的分子靶标和基本机制。在特定目标1中，我们将确定CD1D是否是癌症免疫编辑过程的广义目标。在特定的目标2中，我们将确定并验证其他是癌症免疫修订的其他靶标的基因，这特别强调了我们最近的发现，即这一过程可能会靶向导致CD1D的糖脂配体产生的途径。在特定目标3中，我们将定义这些基因沉默的基础机制。在特定目标4中，我们将确定“编辑器”的途径，以特别强调评估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械洞察力，还可以建立分子准则，以判断已经编辑了肿瘤的程度。