Tsai Hwei-Fang, Hsu Ping-Ning
Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan.
Gradute Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
J Biomed Sci. 2017 May 25;24(1):35. doi: 10.1186/s12929-017-0341-0.
Immune checkpoints or coinhibitory receptors, such as cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1, play important roles in regulating T cell responses, and they were proven to be effective targets in treating cancer. In chronic viral infections and cancer, T cells are chronically exposed to persistent antigen stimulation. This is often associated with deterioration of T cell function with constitutive activation of immune checkpoints, a state called 'exhaustion', which is commonly associated with inefficient control of tumors and persistent viral infections. Immune checkpoint blockade can reinvigorate dysfunctional/exhausted T cells by restoring immunity to eliminate cancer or virus-infected cells. These immune checkpoint blocking antibodies have moved immunotherapy into a new era, and they represent paradigm-shifting therapeutic strategies for cancer treatment. A clearer understanding of the regulatory roles of these receptors and elucidation of the mechanisms of T cell dysfunction will provide more insights for rational design and development of cancer therapies that target immune checkpoints. This article reviews recent advance(s) in molecular understanding of T cell dysfunction in tumor microenvironments. In addition, we also discuss new immune checkpoint targets in cancer therapy.
免疫检查点或共抑制受体，如细胞毒性T淋巴细胞抗原（CTLA）-4和程序性死亡（PD）-1，在调节T细胞反应中发挥重要作用，并且已被证明是治疗癌症的有效靶点。在慢性病毒感染和癌症中，T细胞长期暴露于持续的抗原刺激下。这通常与免疫检查点的组成性激活导致T细胞功能恶化相关，这种状态称为“耗竭”，通常与肿瘤控制效率低下和持续的病毒感染有关。免疫检查点阻断可以通过恢复免疫力来消除癌症或病毒感染细胞，从而使功能失调/耗竭的T细胞恢复活力。这些免疫检查点阻断抗体已将免疫疗法带入一个新时代，它们代表了癌症治疗中具有范式转变意义的治疗策略。更清楚地了解这些受体的调节作用以及阐明T细胞功能障碍的机制，将为合理设计和开发针对免疫检查点的癌症治疗方法提供更多见解。本文综述了肿瘤微环境中T细胞功能障碍分子理解方面的最新进展。此外，我们还讨论了癌症治疗中的新免疫检查点靶点。
