Johnsen A, France J, Sy M S, Harding C V
Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Cancer Res. 1998 Aug 15;58(16):3660-7.
Tumor cells may alter the expression of proteins involved in antigen processing and presentation, allowing them to avoid recognition and elimination by cytotoxic T cells. In this study, reverse transcription-PCR was used to assess the expression in human tumor cell lines of mRNA for multiple components of the class I MHC antigen-processing pathway, including several proteasome subunits that have been implicated in antigen processing but have not been previously examined in this context (e.g., low molecular weight polypeptide proteasome subunit (LMP) 10, proteasome activator (PA) 28alpha, and PA28beta). Deficiencies in the expression of antigen-processing genes were demonstrated in 9 of 27 cell lines, representing a variety of histological types. In some cases, virtually complete deficiencies were observed in the expression of the four genes encoded within the MHC (TAP1, TAP2, LMP2, and LMP7), as well as LMP10, which is encoded outside the MHC. Combined deficiencies of these gene products were common, and marked deficiency of LMP10 was found in five of the nine cell lines with deficits. The existence of deficiencies in the expression of genes at dispersed loci suggested that the basis for the deficiencies was a regulatory mechanism, as opposed to mutation or deletion of these genes. Furthermore, most of the deficiencies were reversed by treatment with IFN-gamma. In contrast to such extreme deficiencies, we found unaltered or only partially decreased expression of PA28alpha and PA28beta in tumor cell lines. Thus, tumors may evade immune surveillance by simultaneously down-regulating multiple components of the MHC-I antigen-processing pathway, thereby altering the processing and presentation of tumor antigens. Expression of essential proteasome subunits, however, may still be maintained.
肿瘤细胞可能会改变参与抗原加工和呈递的蛋白质的表达,从而使其能够逃避细胞毒性T细胞的识别和清除。在本研究中,采用逆转录聚合酶链反应(RT-PCR)来评估人肿瘤细胞系中I类主要组织相容性复合体(MHC)抗原加工途径多个组分的mRNA表达,包括几种与抗原加工有关但此前未在此背景下研究过的蛋白酶体亚基(例如低分子量多肽蛋白酶体亚基(LMP)10、蛋白酶体激活剂(PA)28α和PA28β)。在27个细胞系中的9个中发现了抗原加工基因表达缺陷,这些细胞系代表了多种组织学类型。在某些情况下,观察到MHC内编码的四个基因(TAP1、TAP2、LMP2和LMP7)以及MHC外编码的LMP10的表达几乎完全缺失。这些基因产物的联合缺陷很常见,并且在9个有缺陷的细胞系中的5个中发现LMP10明显缺乏。分散位点的基因表达存在缺陷表明,缺陷的基础是一种调节机制,而不是这些基因的突变或缺失。此外,大多数缺陷通过用γ干扰素治疗得以逆转。与这种极端缺陷形成对比的是,我们发现肿瘤细胞系中PA28α和PA28β的表达未改变或仅部分降低。因此,肿瘤可能通过同时下调MHC-I抗原加工途径的多个组分来逃避免疫监视,从而改变肿瘤抗原的加工和呈递。然而,必需蛋白酶体亚基的表达可能仍得以维持。