Zheng Xiufen, Koropatnick James, Li Mu, Zhang Xusheng, Ling Fengjun, Ren Xiubao, Hao Xishan, Sun Hongtao, Vladau Costin, Franek Jacob A, Feng Biao, Urquhart Bradley L, Zhong Robert, Freeman David J, Garcia Bertha, Min Wei-Ping
Department of Surgery, Pathology, Oncology, Microbiology, and Immunology, London Health Science Centre, London, Ontario, Canada.
J Immunol. 2006 Oct 15;177(8):5639-46. doi: 10.4049/jimmunol.177.8.5639.
Tumor-derived immune suppression is a major impediment to successful immune/gene cancer therapy. In the present study, we describe a novel strategy to disrupt tumor-derived immune suppression by silencing a tolerogenic molecule of tumor origin, IDO, using small interfering RNA (siRNA). Silencing of IDO in B16F10 cells in vitro using IDO-siRNA prevented catabolism of tryptophan and inhibited apoptosis of T cells. IDO-siRNA treatment of B16F10 cells in vitro inhibited subsequent growth, tumor formation, and the size of tumor formed, by those cells when transplanted into host mice. In vivo treatment of B16F10 tumor-bearing mice successfully postponed tumor formation time and significantly decreased tumor size. Furthermore, in vivo IDO-siRNA treatment resulted in recovery of T cells responses and enhancement of tumor-specific killing. Thus, silencing IDO may break tumor-derived immune suppression. These data indicate that RNA interference has potential to enhance cancer therapy by reinstalling anticancer immunity.
肿瘤源性免疫抑制是免疫/基因癌症治疗取得成功的主要障碍。在本研究中，我们描述了一种新策略，即使用小干扰RNA（siRNA）沉默肿瘤来源的耐受性分子吲哚胺2,3-双加氧酶（IDO），以破坏肿瘤源性免疫抑制。在体外使用IDO-siRNA沉默B16F10细胞中的IDO可防止色氨酸分解代谢并抑制T细胞凋亡。体外对B16F10细胞进行IDO-siRNA处理可抑制这些细胞在移植到宿主小鼠后随后的生长、肿瘤形成以及形成肿瘤的大小。对荷B16F10肿瘤小鼠进行体内治疗成功推迟了肿瘤形成时间并显著减小了肿瘤大小。此外，体内IDO-siRNA治疗导致T细胞反应恢复并增强了肿瘤特异性杀伤作用。因此，沉默IDO可能打破肿瘤源性免疫抑制。这些数据表明，RNA干扰有潜力通过重新建立抗癌免疫来增强癌症治疗效果。
