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作者：SCI天天读
SCI
28 May 2024
IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity
(Cancer Discov, IF: 28.2)
Moynihan KD, Kumar MP, Sultan H, et al: IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity. Cancer Discov 10.1158/2159-8290.CD-23–1266, 2024
Abstract 摘要
IL-2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, while others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL-2 to CD8+ T cells, which are key anti-tumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, CD8 cis-targeted IL-2 that demonstrates over 500-fold preference for CD8+ T cells over NK and Treg cells, which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL-2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+ T cells in primates. In mice, an AB248 surrogate demonstrated superior anti-tumor activity and enhanced tolerability as compared to an untargeted IL-2RBy agonist. Efficacy was associated with expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings.
IL-2在不同类型的细胞上发出多效信号，其中一些有助于对肿瘤的治疗活性，而另一些则驱动不想要的活性，如免疫抑制或毒性。我们探索了这样一个理论，即针对 CD8 + T 细胞(它们是关键的抗肿瘤效应物)的 IL-2可以增强其治疗指数。为此，我们开发了 AB248，CD8顺式靶向的 IL-2，其表现出对 CD8 + T 细胞超过 NK 和 Treg 细胞500倍的偏好，这可能分别导致毒性和免疫抑制。AB248重现了 IL-2在体外对 CD8 + T 细胞的作用，并在灵长类动物中诱导了 CD8 + T 细胞的选择性扩增。在小鼠中，与非靶向的 IL-2RBy 激动剂相比，AB248替代物表现出优越的抗肿瘤活性和增强的耐受性。疗效与肿瘤浸润 CD8 + T 细胞的扩增和表型增强有关，包括出现“更好的效应物”群体。这些数据支持 AB248在临床环境中的潜在应用。
SIGNIFICANCE 意义
The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell–selective IL2 for the treatment of cancer.
IL-2治疗的全部潜力仍有待解锁。我们证明，在临床前模型中，通过将 IL-2 信号限制在CD8 + T细胞，毒性可以与抗肿瘤活性解耦，支持开发CD8 + T细胞选择性 IL-2 用于治疗癌症。
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