Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.
Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.
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DOI：
10.1084/jem.20030590
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发表时间：
2003-08-18
期刊：
影响因子：
--
通讯作者：
Restifo NP
中科院分区：
文献类型：
--
作者：
Overwijk WW;Theoret MR;Finkelstein SE;Surman DR;de Jong LA;Vyth-Dreese FA;Dellemijn TA;Antony PA;Spiess PJ;Palmer DC;Heimann DM;Klebanoff CA;Yu Z;Hwang LN;Feigenbaum L;Kruisbeek AM;Rosenberg SA;Restifo NP
许多肿瘤相关抗原源自未突变的“自身”蛋白质。浸润肿瘤沉积物的T细胞识别由肿瘤细胞呈递的自身抗原，并且可以通过疫苗接种在体内扩增。这些T细胞以功能耐受状态存在，因为它们很少导致肿瘤根除。我们发现，即使在过继转移大量对自身/肿瘤抗原gp 100的MHC I类限制性表位具有特异性的T细胞后，小鼠的肿瘤生长和致死率也没有变化。我们试图开发新的策略，其将逆转自身/肿瘤抗原反应性T细胞的功能耐受状态，并能够破坏在治疗开始前建立长达14天的大的（具有垂直直径>50 mm 2的产物）、皮下的、未经操作的、免疫原性差的B16肿瘤。我们已经定义了在该模型中诱导肿瘤消退所必需的三个要素：（a）肿瘤特异性T细胞的过继转移;（B）通过用改变的肽配体而不是天然自身肽进行抗原特异性疫苗接种来刺激T细胞;以及（c）T细胞生长和活化因子的共同施用。细胞，疫苗接种，或细胞因子单独给予或任何两个组合不足以诱导肿瘤破坏。在治愈的小鼠中观察到自身免疫性白癜风。这些发现说明T细胞和IL-2的过继转移可以增强癌症疫苗的功能。此外，这些数据代表了使用对真正的自身/肿瘤抗原特异性的T细胞完全治愈大的、已建立的、免疫原性差的、未经操作的实体瘤的首次证明，并形成了治疗癌症患者的新方法的基础。
Many tumor-associated antigens are derived from nonmutated “self” proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I–restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.
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影响因子：
3.9
作者：
Rosenberg, SA;White, DE
通讯作者：
White, DE
DOI：
10.1006/meth.1997.0461
发表时间：
1997-06-01
期刊：
METHODS-A COMPANION TO METHODS IN ENZYMOLOGY
影响因子：
--
作者：
Overwijk, WW;Surman, DR;Restifo, NP
通讯作者：
Restifo, NP
影响因子：
15.3
作者：
Colella, T A;Bullock, T N;Russell, L B;Mullins, D W;Overwijk, W W;Luckey, C J;Pierce, R A;Restifo, N P;Engelhard, V H
通讯作者：
Engelhard, V H
GP100/PMEL 17是一种鼠肿瘤排斥抗原：使用高亲和力，改变肽配体改变的“自我”反应性，肿瘤T细胞。
DOI：
10.1084/jem.188.2.277
发表时间：
1998-07-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Overwijk WW;Tsung A;Irvine KR;Parkhurst MR;Goletz TJ;Tsung K;Carroll MW;Liu C;Moss B;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
影响因子：
82.9
作者：
Lee, PP;Yee, C;Davis, MM
通讯作者：
Davis, MM