Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction
Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction
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DOI：
10.1182/blood-2007-09-114157
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发表时间：
2009-02-19
期刊：
影响因子：
20.3
通讯作者：
Dranoff, Glenn
中科院分区：
文献类型：
--
作者：
Fonseca, Catia;Soiffer, Robert;Dranoff, Glenn
鉴定有助于转化和与免疫介导的肿瘤破坏相关的癌症抗原是免疫治疗的一个重要目标。为此，我们筛选了小鼠肾细胞癌DNA表达文库，该文库使用的小鼠血清接种了经辐照处理的分泌粒细胞巨噬细胞集落刺激因子（GM-CSF）的肿瘤细胞。检测到多种非突变、过表达的蛋白，这些蛋白在肿瘤细胞迁移、蛋白/核酸稳态、代谢和应激反应中起作用。其中，最常被识别的克隆是蛋白二硫异构酶（PDI）。一名急性髓性白血病患者在接受非清髓性异基因骨髓移植后，用放射的自身分泌gmcsf的肿瘤细胞接种疫苗后获得了完全应答，同样也诱导了人类PDI的高滴度抗体。此外，ERp5是一种密切相关的二硫异构酶，参与主要组织相容性复合体（MHC） I类链相关蛋白a （MICA）的脱落，在多种实体和血液恶性肿瘤患者中也引起了强有力的体液反应，这些患者对GM-CSF分泌肿瘤细胞疫苗或细胞毒性T淋巴细胞相关抗原4 （CTLA-4）的抗体阻断有反应。总之，这些发现揭示了pdi的意想不到的免疫原性，并提出了这些基因产物可能作为治疗性单克隆抗体靶点的可能性。（《血液》杂志2009；113:1681-1688）
The identification of cancer antigens that contribute to transformation and are linked with immune-mediated tumor destruction is an important goal for immunotherapy. Toward this end, we screened a murine renal cell carcinomac DNA expression library with sera from mice vaccinated with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). Multiple nonmutated, overexpressed proteins that function in tumor cell migration, protein/nucleic acid homeostasis, metabolism, and stress responses were detected. Among these, the most frequently recognized clone was protein disulfide isomerase (PDI). High titer antibodies to human PDI were similarly induced in an acute myeloid leukemia patient who achieved a complete response after vaccination with irradiated, autologous GMCSF-secreting tumor cells in the setting of nonmyeloablative allogeneic bone marrow transplantation. Moreover, ERp5, a closely related disulfide isomerase involved in major histocompatibility complex (MHC) class I chain-related protein A (MICA) shedding, also evoked potent humoral reactions in diverse solid and hematologic malignancy patients who responded to GM-CSF secreting tumor cell vaccines or antibody blockade of cytotoxic T lymphocyte associated antigen 4 (CTLA-4). Together, these findings reveal the unexpected immunogenicity of PDIs and raise the possibility that these gene products might serve as targets for therapeutic monoclonal antibodies. (Blood. 2009; 113: 1681-1688)