Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL
Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL
复制标题
DOI：
10.1182/blood-2014-10-609271
复制
发表时间：
2015-05-07
期刊：
影响因子：
20.3
通讯作者：
Mackall, Crystal L.
中科院分区：
文献类型：
--
作者：
Cui, Yongzhi;Onozawa, Masahiro;Mackall, Crystal L.
现在可以对识别肿瘤相关抗原 (TAA) 的 T 细胞受体 (TCR) 和嵌合抗原受体进行改造，使其在多种免疫效应器上表达。针对 TAA 的工程化受体最常在成熟 T 细胞上表达，然而，一些人推测免疫祖细胞上的受体表达可以产生效力增强的 T 细胞。我们生成了表达 TCR 的小鼠（生存素-TCR 转基因 [Sur-TCR-Tg]），该 TCR 在胸腺生成的早期阶段识别小鼠生存素的免疫显性表位 (Sur(20-28))。来自 3 个不同创始人的 Sur-TCR-Tg 小鼠 100% 发生自发性 T 细胞急性淋巴细胞白血病 (T-ALL)。白血病表达 Sur-TCR 并发出响应 Sur(20-28) 肽的信号。在白血病前期小鼠中，我们观察到表达 Sur-TCR 的双阴性胸腺细胞循环增加，并且活化 T 细胞核因子的核转位增加，这与小鼠胸腺中存活蛋白表达诱导的 TCR 信号传导一致。 beta 2M(-/-) Sur-TCR-Tg 小鼠不能有效地将生存素肽呈递到 I 类主要组织相容性复合物上，其白血病发病率显着降低。我们的结论是，胸腺生成早期阶段的 TCR 信号传导介导致癌信号，因此，在胸腺中表达的对胸腺中表达的 TAA 具有特异性的信号传导受体在发育中胸腺细胞上的表达可能会带来肿瘤形成的风险，与插入突变无关。
T-cell receptors (TCRs) and chimeric antigen receptors recognizing tumor-associated antigens (TAAs) can now be engineered to be expressed on a wide array of immune effectors. Engineered receptors targeting TAAs have most commonly been expressed on mature T cells, however, some have postulated that receptor expression on immune progenitors could yield T cells with enhanced potency. We generated mice (survivin-TCR-transgenic [Sur-TCR-Tg]) expressing a TCR recognizing the immunodominant epitope (Sur(20-28)) of murine survivin during early stages of thymopoiesis. Spontaneous T-cell acute lymphoblastic leukemia (T-ALL) occurred in 100% of Sur-TCR-Tg mice derived from 3 separate founders. The leukemias expressed the Sur-TCR and signaled in response to the Sur(20-28) peptide. In preleukemic mice, we observed increased cycling of double-negative thymocytes expressing the Sur-TCR and increased nuclear translocation of nuclear factor of activated T cells, consistent with TCR signaling induced by survivin expression in the murine thymus. beta 2M(-/-) Sur-TCR-Tg mice, which cannot effectively present survivin peptides on class I major histocompatibility complex, had significantly diminished rates of leukemia. We conclude that TCR signaling during the early stages of thymopoiesis mediates an oncogenic signal, and therefore expression of signaling receptors on developing thymocytes with specificity for TAAs expressed in the thymus could pose a risk for neoplasia, independent of insertional mutagenesis.