Survival, persistence, and progressive differentiation of adoptively transferred tumor-reactive T cells associated with tumor regression
Survival, persistence, and progressive differentiation of adoptively transferred tumor-reactive T cells associated with tumor regression
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DOI：
10.1097/01.cji.0000158855.92792.7a
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发表时间：
2005-05-01
影响因子：
3.9
通讯作者：
Robbins, PF
中科院分区：
文献类型：
--
作者：
Huang, JP;Khong, HT;Robbins, PF
目的在自体黑色素瘤反应性肿瘤浸润性淋巴细胞(TILs)过继转移前接受非清髓性化疗的患者中，约有50%的患者观察到了临床反应。最近通过使用针对T细胞受体β链可变区(TRBV)产物的抗体以及对表达的TRBV基因产物的直接测序进行的研究表明，在该试验中的临床反应与过继转移的T细胞的持续水平有关。为了进一步表征过继转移后在体内存活的T细胞，在TIL 2035中发现了5种主要的T细胞克隆型，TIL 2035是过继转移的TIL，与多发性转移的完全消退相关。表达BV1 tr基因产物的最高持久性克隆型在IILA-A23的背景下识别MAGE-6癌症/睾丸抗原。该克隆型在过继移植后的外周血中被检测到超过16个月，表达相对较高的共刺激标记CD28和CD27，并且具有相对于TIL 2035中存在的仅表现短期持续的其他克隆型的较长的端粒。在体内，长期持续的BV1克隆型向终末期效应者的分化似乎比短期持续克隆型的分化更慢。CD28、CD27、CD45RO表达下调，CD57、CD45RA表达上调。这些结果表明，个体TIL克隆型的分化阶段和复制历史可能与其在体内存活和存活的能力有关，而持久克隆型在过继转移后发生了渐进性分化。
Objective clinical responses have been observed in approximately 50% of patients who received non-myeloablative chemotherapy prior to the adoptive transfer of autologous melanoma-reactive tumor-infiltrating lymphocytes (TILs). Recent studies carried out through the use of antibodies directed against T-cell-receptor beta chain variable region (TRBV) products, as well as by direct sequencing of the expressed TRBV gene products, indicated that clinical responses in this trial were associated with the level of persistence of adoptively transferred T cells, In an attempt to further characterize T cells that persist in vivo following adoptive transfer, five dominant T-cell clonotypes were identified in TIL 2035, an adoptively transferred TIL that was associated with the complete regression of multiple metastases. The most highly persistent clonotype, which expressed the BV1 TR gene product, recognized the MAGE-6 cancer/testis antigen in the context of IILA-A23. This clonotype was detected in peripheral blood for over 16 months following adoptive transfer, expressed relatively higher levels of the co-stimulatory markers CD28 and CD27, and possessed telomeres that were long relative to other clonotypes present in TIL 2035 that showed only short-term persistence. The long-term persistent BV1 clonotype appeared to differentiate more slowly toward an end-stage effector in vivo than short-term persistent clonotypes. as manifested by the down regulation of CD28, CD27, and CD45RO and upregulation of CD57 and CD45RA expression on these T cells. These results indicated that the differentiation stage and replicative history of individual TIL clonotypes might be associated with their ability to survive and to persist in vivo, and progressive differentiation of the persistent clonotypes occurred following adoptive transfer.