Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function.
Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function.
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DOI：
10.1097/cji.0b013e318209e7ec
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发表时间：
2011-04
期刊：
影响因子：
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通讯作者：
Radvanyi LG
中科院分区：
文献类型：
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作者：
Hernandez-Chacon JA;Li Y;Wu RC;Bernatchez C;Wang Y;Weber JS;Hwu P;Radvanyi LG
采用高剂量白细胞介素 - 2（IL - 2）扩增的肿瘤浸润淋巴细胞（TIL）进行的过继性T细胞疗法（ACT）是一种对IV期黑色素瘤有前景的免疫疗法，临床缓解率达50%或更高。阻碍该疗法进一步成功的主要问题之一是，目前用于高度扩增用于输注的TIL的方案促使CD8 + T细胞分化为效应细胞，从而丢失关键的共刺激分子，如CD28和CD27。这与体内持久性缺乏有关，原因尚不完全清楚。在本研究中，我们证明在为ACT进行快速扩增期间，人黑色素瘤CD8 + TIL虽丢失CD27和CD28表达，但获得了替代性共刺激分子CD137/4 - 1BB的表达，在较小程度上还获得了CD134/OX40的表达。当用低水平的OKT3抗体通过T细胞受体（TCR）再次激活时，发现扩增后（REP）的TIL对激活诱导的细胞死亡（AICD）高度敏感。然而，使用两种不同的激动性抗 - 4 - 1BB抗体对4 - 1BB进行共连接，可有效防止扩增后CD8 + TIL（包括那些对MART - 1特异的细胞）的AICD，并促进细胞进一步扩增。这与bcl - 2和bcl - xL水平升高以及bim表达降低相关。经4 - 1BB共刺激的扩增后TIL还表达更高水平的溶细胞颗粒蛋白，并对黑色素瘤细胞表现出增强的细胞毒性T淋巴细胞（CTL）活性。最后，当暴露于人类白细胞抗原（HLA）匹配的黑色素瘤细胞时，扩增后CD8 + TIL通过抗 - 4 - 1BB连接可避免细胞死亡。我们的研究结果表明，4 - 1BB共刺激可显著提高黑色素瘤ACT期间TIL的存活率，并增强抗肿瘤溶细胞活性。
Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose IL-2 is a promising form of immunotherapy for Stage IV melanoma having clinical response rates of 50% or more. One of the major problems preventing further success of this therapy is that the current protocols used to highly expand TIL for infusion drive CD8+ T cells to differentiate into effector cells losing key co-stimulatory molecules such as CD28 and CD27. This has been associated with a lack of persistence in vivo for reasons not entirely clear. In this study, we demonstrate that while human melanoma CD8+ TIL lost CD27 and CD28 expression during the rapid expansion for ACT, they gained expression of the alternative co-stimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Post-REP TIL were found to be highly sensitive to activation-induced cell death (AICD) when re-activated through the TCR with low levels of OKT3 antibody. However, co-ligation of 4-1BB using two different agonistic anti-4-1BB antibodies potently prevented AICD of post-REP CD8+ TIL, including those specific for MART-1, and facilitated even further cell expansion. This was correlated with increased levels of bcl-2 and bcl-xL together with decreased bim expression. 4-1BB-co-stimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced CTL activity against melanoma cells. Lastly, post-REP CD8+ TIL were protected from cell death by anti-4-1BB ligation when exposed to HLA-matched melanoma cells. Our results indicate that 4-1BB co-stimulation may significantly improve TIL survival during melanoma ACT and boost anti-tumor cytolytic activity.