PROTO ONCOGENE PML AND TUMOR EVASION OF HOST IMMUNITY

主要组织相容性复合体（MHC） I类抗原所呈现的肽是宿主细胞毒性T淋巴细胞（CTL）在肿瘤细胞上进行免疫识别的主要靶点。很大一部分来自MHC I类阳性上皮的肿瘤完全或选择性地丧失细胞表面MHC I类表达。这可能使肿瘤通过避免MHC I类抗原呈递而逃避免疫识别。虽然导致抗原呈递缺陷的遗传机制在很大程度上是未知的，但很明显，参与抗原呈递的多个基因的表达，如编码内质网（ER）膜上肽转运蛋白的基因（TAP-1和TAP-2）、蛋白体成分LMP-2和LMP-7都会受到影响。我们最近在小鼠中发现了TAP1/2和LMP2/7表达缺陷的复发肿瘤。表达克隆表明，该缺陷可以通过原癌基因PML-F12的过表达来弥补。此外，我们发现内源性PML含有显性负突变。本研究的主要目的是确定PML功能障碍是否导致小鼠和人类肿瘤中的抗原呈递缺陷。我们建议研究PML控制MHC I类抗原加工的多个基因的机制。本研究为了解宿主抗肿瘤免疫逃避肿瘤的基本机制奠定了基础。考虑到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呈递有关。因此，我们的研究可能确定PML是控制MHC I类抗原呈递的主要调节因子。

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.