Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University, Shanghai, 200001, China.
Adv Exp Med Biol. 2020;1248:33-59. doi: 10.1007/978-981-15-3266-5_3.
Immunotherapies that target PD-1/PD-L1 axis have shown unprecedented success in a wide variety of human cancers. PD-1 is one of the key coinhibitory receptors expressed on T cells upon T cell activation. After engagement with its ligands, mainly PD-L1, PD-1 is activated and recruits the phosphatase SHP-2 in proximity to T cell receptor (TCR) and CD28 signaling. This event results in dephosphorylation and attenuation of key molecules in TCR and CD28 pathway, leading to inhibition of T cell proliferation, activation, cytokine production, altered metabolism and cytotoxic T lymphocytes (CTLs) killer functions, and eventual death of activated T cells. Bodies evolve coinhibitory pathways controlling T cell response magnitude and duration to limit tissue damage and maintain self-tolerance. However, tumor cells hijack these inhibitory pathways to escape host immune surveillance by overexpression of PD-L1. This provides the scientific rationale for clinical application of immune checkpoint inhibitors in oncology. The aberrantly high expression of PD-L1 in tumor microenvironment (TME) can be attributable to the "primary" activation of multiple oncogenic signaling and the "secondary" induction by inflammatory factors such as IFN-γ. Clinically, antibodies targeting PD-1/PD-L1 reinvigorate the "exhausted" T cells in TME and show remarkable objective response and durable remission with acceptable toxicity profile in large numbers of tumors such as melanoma, lymphoma, and mismatch-repair deficient tumors. Nevertheless, most patients are still refractory to anti-PD-1/PD-L1 therapy. Identifying the predictive biomarkers and design rational PD-1-based combination therapy become the priorities in cancer immunotherapy. PD-L1 expression, cytotoxic T lymphocytes infiltration, and tumor mutation burden (TMB) are generally considered as the most important factors affecting the effectiveness of PD-1/PD-L1 blockade. The revolution in cancer immunotherapy achieved by PD-1/PD-L1 blockade offers the paradigm for scientific translation from bench to bedside. The next decades will without doubt witness the renaissance of immunotherapy.
免疫疗法靶向 PD-1/PD-L1 轴在多种人类癌症中显示出前所未有的成功。PD-1 是 T 细胞活化后表达的关键共抑制受体之一。与配体（主要是 PD-L1）结合后，PD-1 被激活并募集磷酸酶 SHP-2 接近 T 细胞受体（TCR）和 CD28 信号。这一事件导致 TCR 和 CD28 通路中的关键分子去磷酸化和失活，从而抑制 T 细胞增殖、活化、细胞因子产生、代谢改变和细胞毒性 T 淋巴细胞（CTL）杀伤功能，并最终导致活化的 T 细胞死亡。机体进化出共抑制途径来控制 T 细胞反应的幅度和持续时间，以限制组织损伤并维持自身耐受。然而，肿瘤细胞通过过度表达 PD-L1 来劫持这些抑制途径，从而逃避宿主免疫监视。这为免疫检查点抑制剂在肿瘤学中的临床应用提供了科学依据。肿瘤微环境（TME）中 PD-L1 的异常高表达归因于多种致癌信号的“原发性”激活，以及 IFN-γ 等炎症因子的“继发性”诱导。临床上，靶向 PD-1/PD-L1 的抗体重新激活 TME 中的“耗竭”T 细胞，在大量肿瘤（如黑色素瘤、淋巴瘤和错配修复缺陷肿瘤）中表现出显著的客观反应和持久缓解，且毒性谱可接受。然而，大多数患者仍然对抗 PD-1/PD-L1 治疗有抗性。确定预测生物标志物和设计合理的 PD-1 联合治疗成为癌症免疫治疗的重点。PD-L1 表达、细胞毒性 T 淋巴细胞浸润和肿瘤突变负荷（TMB）通常被认为是影响 PD-1/PD-L1 阻断效果的最重要因素。PD-1/PD-L1 阻断所带来的癌症免疫治疗革命为从基础研究到临床应用的科学转化提供了范例。未来几十年无疑将见证免疫治疗的复兴。
