MOLECULAR CHARACTERIZATION OF DEFECTIVE ANTIGEN-PROCESSING IN HUMAN PROSTATE-CANCER
MOLECULAR CHARACTERIZATION OF DEFECTIVE ANTIGEN-PROCESSING IN HUMAN PROSTATE-CANCER
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DOI：
10.1093/jnci/87.4.280
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发表时间：
1995-02-15
期刊：
影响因子：
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通讯作者：
SIMONS, JW
中科院分区：
文献类型：
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作者：
SANDA, MG;RESTIFO, NP;SIMONS, JW
背景：基因修饰的肿瘤细胞疫苗在包括前列腺癌在内的恶性肿瘤动物模型中显示出有效性。I类主要组织相容性复合体（MHC）组装和在此类疗法的细胞靶点中的功能在确定特异性分泌精氨酸的肿瘤疫苗的功效中是关键的。目的：为了帮助指导人类前列腺癌基因工程疫苗疗法的开发，通过分析前列腺癌细胞中I类MHC组装来评估潜在的免疫抗性途径。方法：通过表型、分子和功能测定表征了转移来源的人前列腺癌细胞系（LNCaP、PPC-1、DU-145、PC-3和大津）和正常前列腺来源的细胞系（TP-2）中的I类MHC组装。通过流式细胞术测量组装的I类MHC和抗原;测定组装组分（I类MHC重链、β（2）-微球蛋白和抗原转运蛋白基因产物TAP-2）的mRNA水平;并使用使用牛痘载体的嵌合重构系统测量抗原加工。通过干扰素γ刺激和用小鼠I类MHC重链cDNA转染来尝试恢复抗原加工。结果如下：与正常前列腺衍生的对照相比，组装的I类MHC在五种前列腺癌细胞系中的两种（LNCaP和PPC-1）中表达不足。PPC-1细胞低表达TAP-2 mRNA，尽管有丰富的I类MHC和β 2-微球蛋白信息。干扰素γ对TAP-2的诱导表明，TAP-2信息的编码序列存在于PPC-1中。对细胞毒性T淋巴细胞（CTL）裂解的抗性显示PPC-1细胞在抗原转运中存在功能缺陷;干扰素γ逆转分子缺陷导致功能性抗原处理恢复。与此相反，LNCaP细胞有能力的抗原运输，但缺乏I类MHC重链功能，尽管丰富的I类MHC RNA，虽然难治干扰素γ的刺激，这种缺陷响应于I类MHC重链cDNA的转染。结论：转移性前列腺癌细胞可以通过缺陷的I类MHC组装的不同机制逃避T细胞识别。TAP-2基因产物在PPC-1细胞中的特异性低表达与先前的肺癌中TAP基因低表达的研究（其同时低表达I类MHC重链）形成对比，并且提供了可能不影响I类MHC重链表达的控制人类癌症中TAP-2基因表达的调节途径的证据。含义：在前列腺癌的基因治疗的临床应用中，这些发现提供了一个理由，专注于策略，可以避免单独依赖于I类MHC介导的肿瘤细胞识别的CTL。
Background: Gene-modified tumor cell vaccines have shown efficacy in animal models of malignancy, including prostate cancer. Class I major histocompatibility complex (MHC) assembly and function in the cellular targets of such therapies is pivotal in determining the efficacy of specific cytokine-secreting tumor vaccines. Purpose: To help guide development of genetically engineered vaccine therapy for human prostate cancer, potential immune resistance pathways were evaluated by analysis of class I MHC assembly in prostate cancer cells. Method: Class I MHC assembly in metastasis-derived human prostate cancer cell lines (LNCaP, PPC-1, DU-145, PC-3, and TSU) and a normal prostate-derived cell line (TP-2) were characterized by phenotypic, molecular, and functional assays. Assembled class I MHC and antigen was measured by flow cytometry; mRNA levels of assembly components (class I MHC heavy chain, beta(2)-microglobulin, and the antigen transporter gene product TAP-2) were determined; and antigen processing was measured with a chimeric reconstituted system using vaccinia vectors. Restoration of antigen processing was attempted by interferon gamma stimulation and by transfection with mouse class I MHC heavy-chain cDNA. Results: Assembled class I MHC was underexpressed in two (LNCaP and PPC-1) of five prostate cancer cell lines compared with normal prostate-derived controls. PPC-1 cells underexpressed TAP-2 mRNA despite abundant class I MHC and beta(2)-microglobulin message. Induction of TAP-2 by interferon gamma indicated that coding sequences for TAP-2 message were present in PPC-1. Resistance to cytotoxic T lymphocytes (CTL) lysis showed a functional defect in antigen transport by PPC-1 cells; reversal of the molecular defect with interferon gamma led to restoration of functional antigen processing. In contrast, LNCaP cells had competent antigen transport but deficient class I MHC heavy-chain function despite abundant class I MHC RNA; though refractory to stimulation by interferon gamma, this defect responded to transfection of class I MHC heavy-chain cDNA. Conclusions: Metastatic prostate cancer cells can escape T-cell recognition via divergent mechanisms of defective class I MHC assembly. The specific underexpression of TAP-2 gene product in PPC-1 cells contrasts with prior studies of TAP gene underexpression in lung cancer (which concurrently underexpressed class I MHC heavy chain) and provides evidence for a regulatory pathway controlling TAP-2 gene expression in human cancers that may not affect class I MHC heavy-chain expression. Implications: In clinical application of gene therapy for prostate cancer, these findings provide a rationale for focusing on strategies that can circumvent sole reliance on class I MHC-mediated tumor cell recognition by CTL.