Akalu Yemsratch T, Rothlin Carla V, Ghosh Sourav
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Immunol Rev. 2017 Mar;276(1):165-177. doi: 10.1111/imr.12522.
Cancer immunotherapy utilizing T-cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non-T-cell-inflamed tumors that lack markers associated with the activation of adaptive anti-tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the development of improved therapies against cancer. Here, we review the TAM receptor tyrosine kinases-TYRO3, AXL, and MERTK-as an emerging class of innate immune checkpoints that participate in key steps of anti-tumoral immunity. Namely, TAM-mediated efferocytosis, negative regulation of dendritic cell activity, and dysregulated production of chemokines collectively favor the escape of malignant cells. Hence, disabling TAM signaling may promote engagement of adaptive immunity and complement T-cell checkpoint blockade.
利用T细胞检查点抑制剂的癌症免疫疗法已取得了巨大的临床成功。然而，这种治疗方式仅对一部分患者有效。无反应的患者往往患有非T细胞炎症性肿瘤，这些肿瘤缺乏与适应性抗肿瘤免疫反应激活相关的标志物。值得注意的是，T细胞对癌细胞的清除严重依赖于先天免疫细胞的最佳活性。因此，识别调节先天免疫细胞功能并促进适应性杀瘤反应参与的新靶点，可能会带来改进的抗癌疗法的发展。在这里，我们综述了TAM受体酪氨酸激酶——TYRO3、AXL和MERTK——作为一类新兴的先天免疫检查点，它们参与抗肿瘤免疫的关键步骤。具体而言，TAM介导的胞葬作用、树突状细胞活性的负调节以及趋化因子的失调产生共同促进了恶性细胞的逃逸。因此，阻断TAM信号可能会促进适应性免疫的参与并补充T细胞检查点阻断。
