Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent.
Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent.
复制标题
淋巴结host的效应CD8+ T细胞植入和抗肿瘤免疫是IL7Rα的依赖性。
DOI：
10.1158/2326-6066.cir-15-0087-t
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发表时间：
2015-12
影响因子：
10.1
通讯作者：
Rubinstein MP
中科院分区：
文献类型：
--
作者：
Johnson CB;Riesenberg BP;May BR;Gilreath SC;Li G;Staveley-O'Carroll KF;Garrett-Mayer E;Mehrotra S;Cole DJ;Rubinstein MP
将活化的肿瘤反应性T细胞转移到小鼠淋巴细胞耗竭宿主中的连续性细胞疗法是一种有前途的癌症治疗选择。T细胞的活化降低IL-7反应性;因此，IL-15通常被认为是这种情况下效应T细胞反应的主要驱动因素。然而，我们发现在淋巴细胞耗竭的宿主中，用IL-12激活的CD 8 + T细胞显示出增强的植入，其最初依赖于宿主IL-7，而不是IL-15。从机制上讲，IL-7反应性增强是由IL-7 R α表达升高引起的，这对于抗肿瘤免疫至关重要。在没有IL-12的情况下可实现升高的IL-7 R α表达，因为用高TCR刺激活化的多克隆CD 8 + T细胞依赖于T细胞IL-7 R α表达和宿主IL-7以实现最大植入。最后，在人CD 8 + T细胞（包括使用临床相关方案产生的TCR修饰的T细胞）活化期间的IL-12调节导致IL-7 R α表达增强。我们的研究结果证明了供体IL-7 R α/宿主IL-7轴对效应CD 8 + T细胞植入的重要性，并提出了改善过继细胞疗法作为癌症治疗的新策略。
Adoptive cellular therapy, in which activated tumor-reactive T cells are transferred into murine lymphodepleted hosts, is a promising cancer treatment option. Activation of T cells decreases IL-7 responsiveness; therefore, IL-15 is generally considered the main driver of effector T cell responses in this setting. However, we found in lymphodepleted hosts that CD8+ T cells activated with IL-12 showed enhanced engraftment that was initially dependent on host IL-7, but not IL-15. Mechanistically, enhanced IL-7 responsiveness was conferred by elevated IL-7Rα expression, which was critical for anti-tumor immunity. Elevated IL-7Rα expression was achievable without IL-12, as polyclonal CD8+ T cells activated with high TCR stimulation depended on T cell IL-7Rα expression and host IL-7 for maximal engraftment. Finally, IL-12 conditioning during the activation of human CD8+ T cells, including TCR-modified T cells generated using a clinically relevant protocol, led to enhanced IL-7Rα expression. Our results demonstrate the importance of the donor IL-7Rα/host IL-7 axis for effector CD8+ T cell engraftment and suggest novel strategies to improve adoptive cellular therapy as a cancer treatment.