Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells.
Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells.
复制标题
DOI：
10.1158/2326-6066.cir-14-0159
复制
发表时间：
2015-02
影响因子：
10.1
通讯作者：
Teague RM
中科院分区：
文献类型：
--
作者：
Berrien-Elliott MM;Yuan J;Swier LE;Jackson SR;Chen CL;Donlin MJ;Teague RM
共抑制受体阻断是一种有前途的策略，以提高对各种人类癌症的T细胞免疫力。然而，许多患者仍然没有从这种治疗中受益，并且应答者经常经历免疫相关的毒性。这些问题突出了需要先进的机制理解，以改善患者的结果，并发现临床相关的生物标志物的治疗效果。然而，检查点阻断治疗期间参与的T细胞内在信号通路尚未明确定义，特别是对于联合方法。使用小鼠模型来研究效应CD 8 + T细胞对肿瘤的反应如何在耐受性环境中增强，我们确定了T-box转录因子T-bet的关键作用。CTLA-4、PD-1和LAG-3的联合阻断诱导了应答肿瘤/自身反应性CD 8 + T细胞中的T-bet表达。使用这种免疫治疗方案根除已建立的白血病依赖于T-bet诱导，这是肿瘤浸润性T细胞产生IFNγ和细胞毒性以及有效运输到播散性肿瘤部位所必需的。这些数据为癌症免疫治疗中检查点阻断的成功提供了新的见解，揭示了T-bet是在其他耐受条件下肿瘤反应性CD 8 + T细胞效应分化的关键转录调节因子。
Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy. However, the T cell-intrinsic signaling pathways engaged during checkpoint blockade treatment are not well defined, particularly for combination approaches. Using a murine model to study how effector CD8+ T-cell responses to tumors may be enhanced in a tolerizing environment, we identified a critical role for the T-box transcription factor T-bet. Combination blockade of CTLA-4, PD-1, and LAG-3 induced T-bet expression in responding tumor/self-reactive CD8+ T cells. Eradication of established leukemia using this immunotherapy regimen depended on T-bet induction, which was required for IFNγ production and cytotoxicity by tumor-infiltrating T cells, and for efficient trafficking to disseminated tumor sites. These data provide new insight into the success of checkpoint blockade for cancer immunotherapy, revealing T-bet as a key transcriptional regulator of tumor-reactive CD8+ T-cell effector differentiation under otherwise tolerizing conditions.