Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Harvard Medical School and Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
Cell Rep. 2020 Nov 17;33(7):108381. doi: 10.1016/j.celrep.2020.108381.
Central to anti-tumor immunity are dendritic cells (DCs), which stimulate long-lived protective T cell responses. Recent studies have demonstrated that DCs can achieve a state of hyperactivation, which is associated with inflammasome activities within living cells. Herein, we report that hyperactive DCs have an enhanced ability to migrate to draining lymph nodes and stimulate potent cytotoxic T lymphocyte (CTL) responses. This enhanced migratory activity is dependent on the chemokine receptor CCR7 and is associated with a unique transcriptional program that is not observed in conventionally activated or pyroptotic DCs. We show that hyperactivating stimuli are uniquely capable of inducing durable CTL-mediated anti-tumor immunity against tumors that are sensitive or resistant to PD-1 inhibition. These protective responses are intrinsic to the cDC1 subset of DCs, depend on the inflammasome-dependent cytokine IL-1β, and enable tumor lysates to serve as immunogens. If these activities are verified in humans, hyperactive DCs may impact immunotherapy.
抗肿瘤免疫的关键是树突状细胞 (DCs)，它能刺激产生具有长期保护作用的 T 细胞反应。最近的研究表明，DCs 可以进入一种超激活状态，这种状态与活细胞内的炎症小体活动有关。在此，我们报告称，超激活的 DC 具有更强的迁移到引流淋巴结并刺激有效细胞毒性 T 淋巴细胞 (CTL) 反应的能力。这种增强的迁移活性依赖于趋化因子受体 CCR7，并且与传统激活或细胞焦亡的 DC 中观察到的独特转录程序无关。我们表明，超激活刺激具有独特的能力，可以诱导对 PD-1 抑制敏感或耐药的肿瘤的持久 CTL 介导的抗肿瘤免疫。这些保护反应是 DCs 的 cDC1 亚群所固有的，依赖于炎症小体依赖性细胞因子 IL-1β，并使肿瘤裂解物作为免疫原。如果这些活性在人类中得到验证，那么超激活的 DC 可能会影响免疫疗法。
