PROTO ONCOGENE PML AND TUMOR EVASION OF HOST IMMUNITY

主要组织相容性复合体(MHC)I类抗原呈递的多肽是宿主细胞毒性T淋巴细胞(CTL)免疫识别的主要靶点。大部分来源于MHC-I类阳性上皮细胞的肿瘤细胞表面MHC-I类表达完全或选择性丧失。这可能允许肿瘤通过避免MHC-I类抗原递呈来逃避免疫识别。虽然导致抗原提呈缺陷的遗传机制很大程度上是未知的，但很明显，参与抗原提呈的多个基因的表达受到影响，例如编码内质网(ER)膜上的多肽转运蛋白(TAP-1和TAP-2)、蛋白质体组分LMP-2和LMP-7的基因。我们最近发现了一例TAP1/2和LMP2/7表达缺陷的小鼠复发性肿瘤。表达克隆显示，原癌基因PML-F12的过度表达可以弥补这一缺陷。此外，我们还发现内源性PML含有显性负突变。这项拟议的研究的主要目标是确定PML功能障碍是否与小鼠和人类肿瘤的抗原提呈缺陷有关。我们建议研究PML控制多个MHC-I类抗原处理基因的机制。我们的研究为了解肿瘤逃避宿主抗肿瘤免疫的基本机制奠定了基础。鉴于PML基因在正常组织中的表达，我们所确定的机制可能与正常组织中的抗原提呈有关。因此，我们的研究可能会将PML确立为控制MHC I类抗原递呈的主调节因子。

The peptides presented by the major histocompatibility complex (MHC) class I antigens are the primary targets on tumor cells for immune recognition by host cytotoxic T lymphocytes (CTL). A large proportion of tumors derived from MHC class I positive epithelia have total or selective loss of cell surface MHC class I expression. This may allow tumors to evade the immune recognition by avoiding MHC class I antigen presentation. While genetic mechanisms that lead to antigen presentation defects are largely unknown, it is clear that expression of multiple genes involved in antigen presentation such as those encode transporters for peptides across endoplasmic reticulum (ER) membrane (TAP-1 and TAP-2), proteosome components LMP-2 and LMP-7 are affected. We have recently characterized a recurrent tumor in mouse that had defective expression of TAP1/2 and LMP2/7. Expression cloning revealed that the defect could be complemented by overexpression of proto-oncogene PML-F12. Moreover, we have found that endogenous PML contains a dominant negative mutation. The main goal of the proposed study is to establish whether malfunction of PML is responsible for antigen presentation defects in murine and human tumors. We proposed to investigate the mechanisms by which PML controls multiple genes devoted to MHC class I antigen processing. Our proposed study is fundamental to understand the basic mechanism for tumor evasion of host anti-tumor immunity. Given expression of PML gene in normal tissue, it is likely the mechanism we have identified is involved in antigen presentation in normal tissue. As such, our study may establish PML as a master regulator controlling MHC class I antigen presentation.