Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
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DOI：
10.1182/blood-2004-09-3742
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发表时间：
2005-10-15
期刊：
影响因子：
20.3
通讯作者：
Hooijberg, E
中科院分区：
文献类型：
--
作者：
Schreurs, MWJ;Hermsen, MAJA;Hooijberg, E
为了在临床环境中获得过继免疫治疗所需的大量T细胞，通过人端粒酶逆转录酶（hTERT）转导延长T细胞寿命是特别感兴趣的。然而，hTERT的组成性表达与恶性转化相关，因此需要在临床应用前详细评估hTERT转导的T细胞的安全性。鉴于此，我们对hTERT转导的MART-1（T细胞1识别的黑素瘤抗原）和人乳头瘤病毒16型（HPV 16）E7特异性人CD 8（+）细胞毒性T淋巴细胞（CTL）进行了广泛的细胞遗传学分析，这些细胞分别对黑素瘤和宫颈癌具有反应性。我们的研究结果，获得（光谱）核型分析和阵列比较基因组杂交，显示轻微的染色体畸变的发展，在hTERT转导的MART-1特异性CTL克隆，而严重的克隆畸变检测hTERT转导的HPV 16 E7特异性CTL克隆。此外，hTERT转导并不能保护CTL免于免疫衰老，因为HPV 16 E7特异性的hTERT转导的CTL克隆在长期培养中显示出降低的功能活性。虽然主要染色体畸变的hTERT转导的CTL的一般频率和我们的观察结果在体内的意义仍然不清楚，在这一点上，目前可用的数据表明，hTERT转导的CTL的临床应用应谨慎进行。
To obtain the large amount of T cells required for adoptive immunotherapy in a clinical setting, T-cell lifespan extension by human telomerase reverse transcriptase (hTERT) transduction is of particular interest. However, constitutive expression of hTERT is associated with malignant transformation and thus warrants a detailed evaluation of the safety of hTERT-transduced T cells before clinical application. In view of this, we performed an extensive cytogenetic analysis of hTERT-transduced MART-1 (melanoma antigen recognized by T cell 1)- and human papillomavirus type 16 (HPV16) E7-specific human CD8(+) cytotoxic T lymphocytes (CTLs), reactive against melanoma and cervical carcinoma, respectively. Our results, obtained by (spectral) karyotyping and array comparative genomic hybridization, showed the development of minor chromosomal aberrations in an hTERT-transduced MART-1-specific CTL clone, whereas severe clonal aberrations were detected in an hTERT-transduced HPV16 E7-specific CTL clone. Furthermore, hTERT transduction did not protect CTLs from immunosenescence, because the HPV16 E7-specific, hTERT-transduced CTL clone showed a decreased functional activity on prolonged culture. Although the general frequency of major chromosomal aberrations in hTERT-transduced CTLs and the in vivo significance of our observations remain still unclear at this point, the currently available data suggest that clinical application of hTERT-transduced CTLs should proceed with caution.