Bai Jie, Gao Zhitao, Li Xiang, Dong Liang, Han Weidong, Nie Jing
Department of Molecular Biology and Bio-Therapeutic, School of Life Science, Chinese PLA General Hospital, Beijing 100853, China.
Oncotarget. 2017 Nov 25;8(66):110693-110707. doi: 10.18632/oncotarget.22690. eCollection 2017 Dec 15.
Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies. However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells. The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-γ signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade. In this review, we describe PD-1 related signaling pathways, essential factors contributing to the resistance of PD-1 blockade, and discuss strategies to increase the efficacy of immunotherapy. Furthermore, we discuss the possibility of combined epigenetic therapy with PD-1 blockade as a potential promising approach for cancer treatment.
免疫检查点阻断剂，如针对程序性死亡蛋白1（PD-1）及其配体（PD-L1）的抑制剂，在过去十年中受到了广泛关注，因为它们在晚期恶性肿瘤中取得了显著的临床疗效。然而，原发性和获得性耐药都成为主要障碍之一，这极大地限制了PD-1/PD-L1阻断疗法的长期效果和广泛应用。PD-1/PD-L1既受细胞信号通路和表观遗传修饰的调节，也对其产生调节作用，从而抑制T细胞和B细胞的增殖及效应功能。肿瘤抗原缺乏和有效的抗原呈递、致癌通路的异常激活、IFN-γ信号通路的突变、免疫抑制性肿瘤微环境（如调节性T细胞、髓源性抑制细胞、M2巨噬细胞和免疫抑制性细胞因子）可导致对PD-1/PD-L1阻断产生耐药。在本综述中，我们描述了与PD-1相关的信号通路、导致PD-1阻断耐药的关键因素，并讨论了提高免疫治疗疗效的策略。此外，我们还讨论了将表观遗传疗法与PD-1阻断联合作为一种潜在的有前景的癌症治疗方法的可能性。
