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干扰素是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活性强的小鼠产生的肿瘤更具免疫原性，这表明免疫系统也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控假说提炼为“癌症免疫编辑假说”，强调免疫在发展中的肿瘤中具有自相矛盾的宿主保护和肿瘤生长作用。虽然癌症免疫编辑假说是基于功能标准(免疫缺陷小鼠和野生型小鼠体内肿瘤生长表型的不同)而形成的，但我们现在试图在分子水平上定义这一过程。使用基因图谱方法，我们最近鉴定了180个差异表达基因，这些基因在免疫缺陷小鼠的高度免疫原性的未经编辑的肉瘤中与来自野生型小鼠的编辑的肉瘤中存在差异表达。CD1d代表这些基因之一，它的表达在编辑后的肉瘤中选择性下调，这种肉瘤是在完整的免疫系统存在的情况下形成的。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体内，会导致逃逸变异体的形成，这些突变体(A)显示CD1d mRNA和蛋白水平显著降低，(B)当注射到未经处理的野生型小鼠中时，逐渐生长。CD1d在F535逃逸变异体中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特定目标来定义癌症免疫编辑的分子靶点和潜在机制。在特定的目标1中，我们将确定CD1d是否是癌症免疫编辑过程的通用靶点。在具体目标2中，我们将识别和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，即这一过程可能额外针对导致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潜在机制(S)。在具体目标4中，我们将确定“编辑”的途径，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，并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.