Kamphorst Alice O, Wieland Andreas, Nasti Tahseen, Yang Shu, Zhang Ruan, Barber Daniel L, Konieczny Bogumila T, Daugherty Candace Z, Koenig Lydia, Yu Ke, Sica Gabriel L, Sharpe Arlene H, Freeman Gordon J, Blazar Bruce R, Turka Laurence A, Owonikoko Taofeek K, Pillai Rathi N, Ramalingam Suresh S, Araki Koichi, Ahmed Rafi
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China, 410013.
Science. 2017 Mar 31;355(6332):1423-1427. doi: 10.1126/science.aaf0683. Epub 2017 Mar 9.
Programmed cell death-1 (PD-1)-targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.
程序性细胞死亡蛋白1（PD-1）靶向疗法可增强T细胞反应，并在多种癌症中显示出疗效，但共刺激分子在这种T细胞拯救过程中的作用仍不清楚。在此，我们证明CD28/B7共刺激途径在慢性病毒感染期间对有效的PD-1治疗至关重要。条件性基因缺失显示，PD-1阻断后CD8 T细胞增殖对CD28存在细胞内在需求。B7共刺激对于荷瘤小鼠的有效PD-1治疗也是必需的。此外，我们发现肺癌患者接受PD-1治疗后血液中增殖的CD8 T细胞主要为CD28阳性。综上所述，这些数据证明了CD8 T细胞拯救需要CD28共刺激，并提示CD28/B7途径在癌症患者的PD-1治疗中具有重要作用。
