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Targeting a self/tumor antigen expressed in the prostate for adoptive T cell immunotherapy of prostate cancer.

机译：靶向前列腺中表达的自身/肿瘤抗原，用于前列腺癌的过继T细胞免疫疗法。

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摘要

Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials. However, poor in vivo persistence and maintenance of anti-tumor activity of transferred tumor-specific T cells remain major problems. Most identified tumor antigens are self-proteins, therefore T cells bearing high avidity TCRs for tumor antigens are often deleted in the thymus and any self/tumor-reactive T cells in the periphery are often eliminated or rendered dysfunction by peripheral tolerance mechanisms. The tumor microenvironment poses additional immunosuppressive obstacles, such as the expression of immunosuppressive cytokines and inhibitory ligands. Transforming growth factor beta (TGFbeta) is a potent immunosuppressive cytokine that is required to prevent autoimmunity and is often present at high levels within tumor microenvironments. Programmed death ligand 1 (PD-L1) is an inhibitory ligand that is expressed by many cancers and it's receptor, PD-1, is expressed by many dysfunctional tumor-infiltrating T cells. One advantage of ACT is the ability to genetically engineer T cells to improve function, such as by transducing high affinity tumor-specific TCRs or disrupting inhibitory signaling pathways. In these studies, we used transgenic mouse models to (1) characterize prostate-specific T cell responses to the normal prostate and (2) evaluate the effects of abrogation of TGFbeta and/or PD-1 signaling in self/tumor specific CD8 T cells for use in ACT of prostate cancer.;First, we found that prostate-specific CD8 T cells were subjected to both central and peripheral deletion. Using an adoptive transfer model, we found that in vivo immunization and/or pre-activation of prostate-specific CD8 T cells resulted in prostate infiltration but no subsequent prostate damage. Second, we found that abrogation of TGFbeta signaling increased persistence and augmented anti-tumor activity of self/tumor specific CD8 T cells in a murine model of autochthonous prostate cancer. However, over time, prostate infiltrating T cells became dysfunctional and expressed high levels of PD-1. Moreover, blockade of PD-1 signaling did not rescue or further sustain the function of these cells. These findings reveal that when targeting a tumor antigen that is also expressed as a self-protein, substantive obstacles in addition to TGFbeta and PD-1 are operative within the tumor microenvironment.
机译：在临床试验中，正在积极地采用过继性T细胞疗法（ACT）来治疗已确立的癌症。然而，差的体内持久性和转移的肿瘤特异性T细胞的抗肿瘤活性维持仍然是主要问题。多数鉴定出的肿瘤抗原是自身蛋白，因此带有高抗原性TCR的T细胞通常会在胸腺中缺失，并且周围的任何自身/肿瘤反应性T细胞通常会被周围的耐受机制消除或功能障碍。肿瘤微环境带来了额外的免疫抑制障碍，例如免疫抑制细胞因子和抑制性配体的表达。转化生长因子β（TGFbeta）是一种有效的免疫抑制细胞因子，是预防自身免疫所必需的，并且通常以高水平存在于肿瘤微环境中。程序性死亡配体1（PD-L1）是一种抑制性配体，在许多癌症中均有表达，而其受体PD-1在许多功能失调的肿瘤浸润性T细胞中均有表达。 ACT的一项优势是能够对T细胞进行基因改造，从而改善其功能，例如通过转导高亲和力的肿瘤特异性TCR或破坏抑制性信号传导途径。在这些研究中，我们使用转基因小鼠模型来（1）​​表征前列腺特异性T细胞对正常前列腺的反应，以及（2）评估TGFbeta和/或PD-1信号消除在自身/肿瘤特异性CD8 T细胞中的作用首先，我们发现前列腺特异的CD8 T细胞受到中央和外周缺失。使用过继转移模型，我们发现前列腺特异性CD8 T细胞的体内免疫和/或预激活导致前列腺浸润，但没有随后的前列腺损害。第二，我们发现废除TGFbeta信号在自体前列腺癌的鼠模型中增加了自身/肿瘤特异性CD8 T细胞的持久性并增强了其抗肿瘤活性。但是，随着时间的流逝，前列腺浸润性T细胞功能失调并表达高水平的PD-1。而且，PD-1信号转导的阻断不能拯救或进一步维持这些细胞的功能。这些发现表明，当靶向也表达为自身蛋白的肿瘤抗原时，除了TGFβ和PD-1外，实质性障碍还在肿瘤微环境中起作用。

著录项

  • 作者

    Chou, Cassie K.;

  • 作者单位

    University of Washington.;

  • 授予单位 University of Washington.;
  • 学科 Health Sciences Immunology.;Health Sciences Oncology.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 84 p.
  • 总页数 84
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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