Herbst Roy S, Soria Jean-Charles, Kowanetz Marcin, Fine Gregg D, Hamid Omid, Gordon Michael S, Sosman Jeffery A, McDermott David F, Powderly John D, Gettinger Scott N, Kohrt Holbrook E K, Horn Leora, Lawrence Donald P, Rost Sandra, Leabman Maya, Xiao Yuanyuan, Mokatrin Ahmad, Koeppen Hartmut, Hegde Priti S, Mellman Ira, Chen Daniel S, Hodi F Stephen
Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, Connecticut 06520, USA.
Gustave Roussy South-Paris University, 114 Rue Edouard Vaillant, 94805 Villefuij, Cedex, France.
Nature. 2014 Nov 27;515(7528):563-7. doi: 10.1038/nature14011.
The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.
人类癌症的发展是一个多步骤过程，其特征是驱动或反映肿瘤进展的遗传和表观遗传改变不断积累。这些变化使癌细胞与其正常对应细胞区分开来，从而使肿瘤被免疫系统识别为外来物。然而，肿瘤很少会自发被排斥，这反映出它们维持免疫抑制微环境的能力。程序性死亡配体1（PD-L1；也称为B7-H1或CD274）在许多癌症和免疫细胞上表达，通过结合程序性死亡-1（PD-1）和B7.1（CD80）在阻断“癌症免疫循环”中发挥重要作用，而这两者都是T淋巴细胞激活的负调节因子。PD-L1与其受体的结合会抑制T细胞迁移、增殖和细胞毒性介质的分泌，并限制肿瘤细胞杀伤。PD-L1-PD-1轴不仅在癌症中，而且在微生物感染期间，都能保护宿主免受过度活跃的T效应细胞的影响。因此，阻断PD-L1应该会增强抗癌免疫力，但关于疗效的预测因素却知之甚少。本研究旨在评估使用工程化人源化抗体MPDL3280A抑制PD-L1的安全性、活性和生物标志物。我们在此表明，在多种癌症类型中，在表达高水平PD-L1的肿瘤患者中观察到了反应（根据实体瘤疗效评价标准1.1版进行评估），特别是当肿瘤浸润免疫细胞表达PD-L1时。此外，反应与基线肿瘤标本中1型辅助性T细胞（TH1）基因表达、CTLA4表达以及缺乏趋化因子（CX3CL1）有关。总之，这些数据表明，MPDL3280A在那些预先存在的免疫被PD-L1抑制且在抗体治疗后得以恢复的患者中最为有效。
