PROTO ONCOGENE PML AND TUMOR EVASION OF HOST IMMUNITY

由主要组织相容性复合体（MHC）I类抗原呈递的肽是宿主细胞毒性T淋巴细胞（CTL）免疫识别肿瘤细胞的主要靶点。 大部分源自MHC I类阳性上皮的肿瘤具有细胞表面MHC I类表达的全部或选择性丧失。 这可能允许肿瘤通过避免MHC I类抗原呈递来逃避免疫识别。 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受到影响，例如编码跨内质网（ER）膜的肽转运蛋白（TAP-1和TAP-2）、蛋白体组分LMP-2和LMP-7的那些基因。 我们最近的特点是复发性肿瘤小鼠有缺陷的表达TAP 1/2和LMP 2/7。表达克隆显示，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。拟定研究的主要目的是确定PML功能障碍是否是小鼠和人肿瘤中抗原呈递缺陷的原因。 我们建议研究PML控制多个致力于MHC I类抗原加工的基因的机制。 我们的研究对于理解肿瘤逃避宿主抗肿瘤免疫的基本机制具有重要意义。 考虑到PML基因在正常组织中的表达，我们已经确定的机制可能涉及正常组织中的抗原呈递。 因此，我们的研究可能建立PML作为一个主调节控制MHC I类抗原呈递。

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.