The Molecular and Cellular Basis of Cancer Immunoediting

描述（由申请人提供）：我们发现淋巴细胞和IFN-γ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，在免疫缺陷小鼠中产生的肿瘤比来自免疫活性小鼠的肿瘤更具免疫原性，这表明免疫系统也选择表达降低的免疫原性的肿瘤变体。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”，强调免疫对发展中肿瘤的矛盾宿主保护和肿瘤塑造作用。鉴于癌症免疫编辑假说是基于功能标准（免疫缺陷小鼠与野生型小鼠肿瘤的体内生长表型不同）制定的，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，我们最近确定了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。CD 1d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。将表达高水平CD 1d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逃逸变体的形成，这些逃逸变体（a）显示出显著降低的CD 1d mRNA和蛋白水平，（B）当注射到未经操作的野生型小鼠中时进行性生长。F535逃逸变体中CD 1d的强化表达恢复了它们的高免疫原性。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CD 1d是否是癌症免疫编辑过程的通用靶标。在具体目标2中，我们将确定和验证其他基因，这些基因是癌症免疫编辑的额外靶点，特别强调我们最近的发现，即该过程可能额外靶向导致CD 1d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，我们将确定途径“编辑者”，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，也可能建立分子指南来判断肿瘤被编辑的程度。

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.