Department of Informative Clinical Medicine, First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Immunology. 2015 Apr;144(4):621-30. doi: 10.1111/imm.12413.
Toll-like receptor (TLR) agonists have been shown to have anti-tumour activity in basic research and clinical studies. However, TLR agonist monotherapy does not sufficiently eliminate tumours. Activation of the innate immune response by TLR agonists is effective at driving adaptive immunity via interleukin-12 (IL-12) or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, transforming growth factor-β, and indoleamine 2,3-dioxygenase (IDO). In the present study, we evaluated the anti-cancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of IDO activity. The administration of IMQ in IDO knockout (KO) mice inoculated with tumour cells significantly suppressed tumour progression compared with that in wild-type (WT) mice, and improved the survival rate. Moreover, injection with IMQ enhanced the tumour antigen-specific T helper type 1 response in IDO-KO mice with tumours. Combination therapy with IMQ and an IDO inhibitor also significantly inhibited tumour growth. Our results indicated that the enhancement of IDO expression with TLR agonists in cancer treatment might impair host anti-tumour immunity while the inhibition of IDO could enhance the therapeutic efficacy of TLR agonists via the increase of T helper type 1 immune response.
Toll 样受体 (TLR) 激动剂在基础研究和临床研究中已被证明具有抗肿瘤活性。然而，TLR 激动剂单药治疗并不能充分消除肿瘤。TLR 激动剂激活先天免疫反应通过白细胞介素-12 (IL-12) 或白细胞介素-1 (IL-1) 有效地驱动适应性免疫，但同时诱导免疫抑制细胞因子和其他分子，包括白细胞介素-10 (IL-10)、转化生长因子-β (TGF-β) 和吲哚胺 2,3-双加氧酶 (IDO)，会产生拮抗作用。在本研究中，我们评估了 TLR7 激动剂咪喹莫特 (IMQ) 在不存在 IDO 活性的情况下的抗癌作用。在接种肿瘤细胞的 IDO 敲除 (KO) 小鼠中给予 IMQ 治疗可显著抑制肿瘤进展，与野生型 (WT) 小鼠相比，存活率也得到提高。此外，在有肿瘤的 IDO-KO 小鼠中注射 IMQ 增强了肿瘤抗原特异性辅助性 T 细胞 1 型反应。IMQ 与 IDO 抑制剂联合治疗也显著抑制了肿瘤生长。我们的研究结果表明，TLR 激动剂增强 IDO 表达可能会损害宿主抗肿瘤免疫，而抑制 IDO 可能会通过增加辅助性 T 细胞 1 型免疫反应来增强 TLR 激动剂的治疗效果。
