Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients.
Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients.
复制标题
DOI：
10.1158/0008-5472.can-07-6838
复制
发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Johanning GL
中科院分区：
文献类型：
--
作者：
Wang-Johanning F;Radvanyi L;Rycaj K;Plummer JB;Yan P;Sastry KJ;Piyathilake CJ;Hunt KK;Johanning GL
近期证据表明，人类癌细胞会重新激活潜伏的人类内源性逆转录病毒（HERV）蛋白的表达。然而，癌症患者对表达的HERV成分产生新的免疫反应的程度尚不清楚。在这项研究中，我们确定了HERV - K env在人类乳腺癌（BC）中的表达程度，以及在乳腺癌患者中是否能发现针对HERV - K的体液免疫和细胞介导的免疫。我们发现88%的乳腺癌组织（n = 119）中有HERV - K env蛋白表达，而在正常乳腺组织（n = 76）中没有。酶联免疫吸附测定（ELISA）筛选试验在大部分乳腺癌患者中检测到显著滴度的抗HERV - K env IgG。在乳腺癌患者的外周血单个核细胞（PBMC）中，用HERV - K env SU抗原脉冲的自体树突状细胞刺激后，也检测到了针对HERV - K的T细胞反应。这些反应包括T细胞增殖的诱导（P = 0.0043）、通过酶联免疫斑点法检测到的干扰素 - γ产生（P < 0.0001）以及多重细胞因子分泌（P = 0.0033）。多重细胞因子分析发现了一种辅助性T细胞1型细胞因子反应，包括在体外用HERV - K抗原刺激乳腺癌患者的PBMC时白细胞介素（IL）- 2（P = 0.0109）、IL - 6（P = 0.0396）、IL - 8（P = 0.0169）和IP - 10（P = 0.0045）的分泌。我们还发现了HERV - K特异性细胞毒性T淋巴细胞（CTL），它们能够裂解乳腺癌患者中表达HERV - K env蛋白的靶细胞，但在没有癌症的正常女性对照中则不能。这些发现表明，逆转录病毒基因产物能够作为肿瘤相关抗原，激活乳腺癌患者的T细胞和B细胞反应。
Recent evidence indicates that human cancer cells reactivate the expression of latent human endogenous retroviral (HERV) proteins. However, the extent to which cancer patients mount de novo immune responses against expressed HERV elements is unclear. In this study, we determined the extent of HERV-K env expression in human breast cancer (BC) and whether both humoral and cell-mediated immunity against HERV-K can be found in BC patients. We found HERV-K env protein expression in 88% of BC (n = 119) but not in normal breast (n = 76) tissues. ELISA screening assays detected significant titers of anti–HERV-K env IgG in a large proportion of BC patients. T-cell responses against HERV-K were also detected in peripheral blood mononuclear cells (PBMC) from BC patients stimulated with autologous dendritic cells pulsed with HERV-K env SU antigens. These responses included induction of T-cell proliferation (P = 0.0043), IFN-γ production measured by enzyme-linked immunospot (P < 0.0001), and multiplex cytokine secretion (P = 0.0033). Multiplex cytokine analysis found a T-helper 1 cytokine response, including interleukin (IL)-2 (P = 0.0109), IL-6 (P = 0.0396), IL-8 (P = 0.0169), and IP-10 (P = 0.0045) secretion during in vitro stimulation of BC PBMC with HERV-K antigen. We also found HERV-K–specific CTLs that were capable of lysing target cells expressing HERV-K env protein in BC patients but not in normal female controls without cancer. These findings suggest that retroviral gene products are capable of acting as tumor-associated antigens activating both T-cell and B-cell responses in BC patients.