Incorporation of Transmembrane Hydrophobic Mutations in the TCR Enhance Its Surface Expression and T Cell Functional Avidity
Incorporation of Transmembrane Hydrophobic Mutations in the TCR Enhance Its Surface Expression and T Cell Functional Avidity
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DOI：
10.4049/jimmunol.1103020
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发表时间：
2012-06-01
影响因子：
4.4
通讯作者：
Cohen, Cyrille J.
中科院分区：
文献类型：
--
作者：
Haga-Friedman, Astar;Horovitz-Fried, Miryam;Cohen, Cyrille J.
TCR基因转移代表了一种有效的方法来重定向T淋巴细胞的特异性用于治疗目的。最近成功的临床试验强调了这种方法的潜力，其中外源TCR的有效表达与T细胞活性的功效直接相关。还已经证明，TCR表现出缺乏与其跨膜（TM）区中带正电荷的残基的存在相关的稳定性。在这项研究中，我们设计了一种新颖的方法，通过增加TCR α TM区的疏水性来选择性地提高外源性TCR的稳定性。在进化上允许的位置处引入疏水残基导致TCR链的表面表达增强，从而导致细胞亲合力和抗肿瘤TCR活性的改善。此外，该策略成功应用于不同的TCR，从而能够靶向来自不同组织学的人类肿瘤。我们还表明，这些疏水突变与另一种TCR增强方法的组合进一步改善了TCR的表达和功能。总之，这些发现提供了关于TCR TM组合物的信息，其可用于改善基于TCR基因转移的治疗。免疫学杂志，2012，188：5538-5546。
TCR-gene transfer represents an effective way to redirect the specificity of T lymphocytes for therapeutic purposes. Recent successful clinical trials have underscored the potential of this approach in which efficient expression of the exogenous TCR has been directly linked to the efficacy of T cell activity. It has been also demonstrated that the TCR exhibits a lack of stability associated with the presence of positively charged residues in its transmembrane (TM) region. In this study, we designed an original approach selectively to improve exogenous TCR stability by increasing the hydrophobic nature of the TCR alpha TM region. Incorporation of hydrophobic residues at evolutionarily permissive positions resulted in an enhanced surface expression of the TCR chains, leading to an improved cellular avidity and anti-tumor TCR activity. Furthermore, this strategy was successfully applied to different TCRs, enabling the targeting of human tumors from different histologies. We also show that the combination of these hydrophobic mutations with another TCR-enhancing approach further improved TCR expression and function. Overall, these findings provide information regarding TCR TM composition that can be applied for the improvement of TCR-gene transfer-based treatments. The Journal of Immunology, 2012, 188: 5538-5546.