Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Exp Med. 2010 Sep 27;207(10):2195-206. doi: 10.1084/jem.20101123. Epub 2010 Sep 13.
The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell-dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.
凋亡抑制蛋白（IAPs）最近被证明可以调节肿瘤坏死因子（TNF）家族受体下游的核因子κB（NF-κB）信号通路，使它们成为几种癌细胞系中重要的生存因子，这可以通过几种新型小分子 IAP 拮抗剂的细胞毒性活性来证明。除了在癌症中的作用外，越来越多的证据表明 IAP 在免疫中具有重要功能；然而，IAP 拮抗剂对肿瘤免疫反应的影响尚不清楚。在这项研究中，我们研究了 IAP 拮抗作用对体外 T 细胞功能和体内肿瘤疫苗的影响。我们发现 IAP 拮抗剂可以增强人类和小鼠 T 细胞对生理相关刺激的反应。IAP 拮抗剂的活性取决于 NF-κB2 信号的激活，这一机制与癌细胞中细胞毒性活性的机制相似。我们进一步表明，IAP 拮抗剂可以增强体内预防性和治疗性抗肿瘤疫苗的效果。这些发现表明 IAP 在调节 T 细胞依赖性反应中起重要作用，并表明使用小分子拮抗剂靶向 IAP 可能是开发针对癌症的新型免疫调节治疗策略的一种策略。
