Azuma Takeshi, Yao Sheng, Zhu Gefeng, Flies Andrew S, Flies Sarah J, Chen Lieping
Department of Dermatology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Blood. 2008 Apr 1;111(7):3635-43. doi: 10.1182/blood-2007-11-123141. Epub 2008 Jan 25.
B7-H1 is an immunoglobulin-like immune suppressive molecule broadly detectable on the majority of human and rodent cancers, and its functions have been attributed to delivering an inhibitory signal to its counter-receptor programmed death-1 (PD-1) on T cells. Here we report that B7-H1 on cancer cells receives a signal from PD-1 to rapidly induce resistance against T cell-mediated killing because crippling signaling capacity of B7-H1 but not PD-1 ablates this resistance. Importantly, loss of B7-H1 signaling is accompanied by increased susceptibility to immune-mediated tumoricidal activity. In addition to resistance against T-cell destruction, B7-H1+ cancer cells also become refractory to apoptosis induced by Fas ligation or the protein kinase inhibitor Staurosporine. Our study reveals a new mechanism by which cancer cells use a receptor on immune cells as a ligand to induce resistance to therapy.
B7-H1是一种免疫球蛋白样免疫抑制分子，在大多数人类和啮齿动物癌症中均可广泛检测到，其功能被认为是向T细胞上的配对受体程序性死亡1（PD-1）传递抑制信号。在此我们报告，癌细胞上的B7-H1从PD-1接收信号以快速诱导对T细胞介导杀伤的抗性，因为削弱B7-H1而非PD-1的信号传导能力可消除这种抗性。重要的是，B7-H1信号的缺失伴随着对免疫介导的杀瘤活性敏感性的增加。除了对T细胞破坏具有抗性外，B7-H1阳性癌细胞对Fas配体连接或蛋白激酶抑制剂星形孢菌素诱导的凋亡也变得难治。我们的研究揭示了一种新机制，即癌细胞利用免疫细胞上的一种受体作为配体来诱导对治疗的抗性。
