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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition
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Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition

机译：靶向淋巴毒素介导的负选择预防具有遗传易感性小鼠的前列腺癌

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摘要

The identification of individuals genetically susceptible to cancer calls for preventive measures to minimize the cancer risk in these high-risk populations. Immune prevention is made necessary by the anticipated health threat, but lack of enough high-affinity T cells against tumor-associated antigens and the unpredictability of tumor antigens make antigen-based immune prevention untenable for cancer. To address this issue, we explored a non-antigen-based cancer immune prevention strategy using the transgenic adenocarcinoma of mouse prostate model that spontaneously develops prostate cancer with 100% penetrance. We show that targeted mutation of the lymphotoxin α (LTα) gene efficiently rescued tumor-reactive T cells, drastically reduced cancer incidence, and almost completely ablated metastasis. Remarkably, short-term treatments with the fusion protein consisting of constant region of IgG and extracellular domain of lymphotoxin β receptor (LTβRIg) interrupted clonal deletion, reduced the size of the primary cancer, and completely prevented metastasis later in life. Our data demonstrated the value of non-antigen-based immune prevention for those with a genetic predisposition to cancer.
机译：对遗传上易患癌症的个体的鉴定要求采取预防措施，以最大程度地降低这些高危人群的癌症风险。预期的健康威胁使得必须进行免疫预防，但是缺乏足够的针对肿瘤相关抗原的高亲和力T细胞，以及肿瘤抗原的不可预测性，使得基于抗原的免疫预防无法抵抗癌症。为了解决这个问题，我们使用小鼠前列腺模型的转基因腺癌​​探索了一种非基于抗原的癌症免疫预防策略，该模型可自发发展出100％渗透率的前列腺癌。我们显示淋巴毒素α（LTα）基因的靶向突变有效地挽救了肿瘤反应性T细胞，大大降低了癌症的发病率，并几乎完全消除了转移。值得注意的是，由IgG恒定区和淋巴毒素β受体（LTβRIg）的胞外域组成的融合蛋白的短期治疗可中断克隆的缺失，减小原发癌的大小，并在以后的生命中完全防止转移。我们的数据证明了基于非抗原的免疫预防对那些具有遗传易感性癌症的人的价值。

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  • 作者

    Penghui Zhou; Xianfeng Fang; Beth A. McNally; Ping Yu; Mingzhao Zhu; Yang-Xin Fu; Lizhong Wang; Yang Liu; Pan Zheng;

  • 作者单位

    Division of Immunotherapy, Departments of Surgery, Internal Medicine, and Pathology, University of Michigan School of Medicine and Cancer Center, Ann Arbor, Ml 48109;

    lnstitute of Biophysics, Chinese Academy of Science, Beijing 100101, China;

    Division of Immunotherapy, Departments of Surgery, Internal Medicine, and Pathology, University of Michigan School of Medicine and Cancer Center, Ann Arbor, Ml 48109;

    Department of Pathology, University of Chicago School of Medicine, Chicago, IL 60636;

    Department of Pathology, University of Chicago School of Medicine, Chicago, IL 60636;

    Department of Pathology, University of Chicago School of Medicine, Chicago, IL 60636;

    Division of Immunotherapy, Departments of Surgery, Internal Medicine, and Pathology, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109;

    Division of Immunotherapy, Departments of Surgery, Internal Medicine, and Pathology, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109 109 Zina Pitcher Place, Ann Arbor, MI 48109;

    Division of Immunotherapy, Departments of Surgery, Internal Medicine, and Pathology, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    prostate cancer mouse model; T-cell development; T-cell effector function; non-antigen-based immune prevention;

    机译：前列腺癌小鼠模型;T细胞发育;T细胞效应子功能;基于非抗原的免疫预防;

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