Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways:: β2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors
Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways:: β2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors
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DOI：
10.1034/j.1399-0039.2003.00020.x
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发表时间：
2003-03-01
期刊：
影响因子：
--
通讯作者：
Garrido, F
中科院分区：
文献类型：
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作者：
Cabrera, CM;Jiménez, P;Garrido, F
在不同类型的肿瘤中导致MHC I类表达缺失的机制尚不完全清楚。因此，我们研究了结肠直肠癌，以阐明逃避t细胞免疫反应的具体机制。我们选择MHC I类表达完全缺失的肿瘤，用免疫组化染色和抗hla单克隆抗体（mAb）对124例结直肠癌进行研究。124例肿瘤中有14例（11%）表现出HLA I类完全缺失的表型。微卫星不稳定性（MSI）分析也进行了相同的肿瘤样本。应用逆转录聚合酶链式反应（RT-PCR）分析微解剖肿瘤样本中β(2) -微球蛋白（β (2) m）、HLA-A、B和C抗原、抗原加工相关转运蛋白1 （TAP1）、TAP2、低分子量蛋白2 （LMP2）和LMP7的表达。14例微卫星不稳定阳性（MSI+）和W6/32单克隆抗体阴性肿瘤中有4例显示β (2) m双等位基因失活和HLA I类重链在细胞质中积累。MSI阴性(MSI-)/W6/32单克隆抗体阴性肿瘤抗原加工机制（APM）组分表达发生改变。10例肿瘤中9例出现LMP7基因下调，4例出现TAP2基因异常。实验组重链和β (2) m mRNA表达正常。在结直肠癌中，两种主要机制似乎是导致MHC表面表达完全丧失的原因（β (2) m突变和LMP7/TAP2下调），这可能导致免疫应答过程中T淋巴细胞识别失败。精确识别导致HLA I类异常的分子缺陷将对接受基于t细胞的特异性免疫治疗的患者具有重要意义。
The mechanisms that lead to loss of MHC class I expression in different types of tumors are not yet fully known. Accordingly, we studied colorectal carcinomas to elucidate the specific mechanisms of evasion of the T-cell immune response. We selected tumors with total loss of MHC class I expression and studied 124 colorectal carcinomas with immunohistochemical staining and anti-HLA monoclonal antibodies (mAb). Fourteen of 124 (11%) tumors exhibited a phenotype with HLA class I total loss. Microsatellite instability (MSI) analysis was also carried out in the same tumor samples. The expression of beta(2) -microglobulin (beta(2) m), HLA-A, B, and C antigens, transporter associated with antigen processing 1 (TAP1), TAP2, low-molecular-weight protein 2 (LMP2), and LMP7 were analyzed using reverse-transcription polymerase chain reaction (RT-PCR) in microdissected tumor samples. Four of 14 microsatellite instability-positive (MSI+ ) and W6/32 mAb-negative tumors showed biallelic inactivation of beta(2) m and accumulation of HLA class I heavy chain in the cytoplasm. MSI-negative (MSI- )/W6/32 mAb-negative tumors presented alterations in the expression of components of the antigen processing machinery (APM). Nine of 10 tumor samples showed LMP7 gene downregulation, and four of 10 presented TAP2 dysregulation. This group apparently expressed normal levels of heavy chain and beta(2) m mRNA. Two major mechanisms in colorectal cancer appear to be responsible for the total loss of MHC surface expression (beta(2) m mutations and LMP7/TAP2 downregulation) that may contribute to the failure of T lymphocyte recognition during an immune response. The precise identification of the molecular defects that underlie HLA class I abnormalities will have important implications for patients receiving T-cell-based specific immunotherapy.