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IFNγ作为有效的癌症免疫监视系统发挥作用，以保护小鼠免受自发性和化学诱导的原发性肿瘤的发展。然而，我们还发现，免疫缺陷小鼠中产生的肿瘤比免疫功能正常小鼠中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体。这些观察结果使我们将癌症免疫监视假说细化为“癌症免疫编辑假说”，该假说强调免疫对发展中的肿瘤的矛盾的宿主保护和肿瘤塑造作用。虽然癌症免疫编辑假说是根据功能标准（免疫缺陷小鼠与野生型小鼠的肿瘤体内生长表型不同）制定的，但我们现在寻求在分子水平上定义该过程。使用基因分析方法，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、未编辑的肉瘤中与野生型小鼠的编辑肉瘤中存在差异表达。 CD1d 代表这些基因之一，其表达在完整免疫系统存在下形成的编辑肉瘤中选择性下调。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的小鼠中，会导致逃逸变体的形成，这些变体 (a) 显示 CD1d mRNA 和蛋白质水平显着降低，并且 (b) 当注射到未操作的野生小鼠中时逐渐生长型老鼠。 F535 逃逸变体中 CD1d 的强制表达恢复了其高免疫原性。利用这些新的观察结果，我们现在将通过追求以下四个具体目标来定义癌症免疫编辑的分子靶点和潜在机制。在具体目标 1 中，我们将确定 CD1d 是否是癌症免疫编辑过程的通用靶标。在具体目标 2 中，我们将鉴定并验证作为癌症免疫编辑额外靶点的其他基因，特别强调我们最近的发现，即该过程可能另外针对导致 CD1d 糖脂配体产生的途径。在具体目标 3 中，我们将定义这些基因沉默的机制。在具体目标 4 中，我们将确定通路“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见解，并可能建立分子指南来判断肿瘤编辑的程度。