Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
J Immunother. 2011 Apr;34(3):264-9. doi: 10.1097/CJI.0b013e318209eed4.
Topical imiquimod cream (trade name: Aldara) is a Toll-like receptor (TLR) 7 agonist that is approved for the treatment of cutaneous tumors. Aldara is also used as a vaccine adjuvant in clinical trials in patients with glioma and other tumors. The main mechanism of action ascribed to Aldara has been the local activation of TLR7(+) cells near the application site. Here we report the unexpected finding that Aldara has therapeutic and immunomodulatory activity as a single agent in mice bearing intracranial tumors. Repeated administration of Aldara onto the skin significantly increased the survival of mice bearing intracranial GL261 glioma and EMT6 breast carcinoma. Aldara treatment was associated with a reduction in the number CD4(+)Foxp3(+) regulatory T cells in the blood and brain tumor site. Mice treated with Aldara exhibited a generalized lymphopenia in the blood amidst an increase in brain tumor infiltrating CD4(+) and CD8(+) T cells and dendritic cells. Brain-infiltrating CD8(+) T cells were tumor reactive as demonstrated by degranulation and interferon-γ secretion in a GL261-dependent manner. In addition, soluble imiquimod directly inhibited the proliferation of GL261 cells in a TLR7-independent manner. This is the first report demonstrating that topical application of imiquimod can enhance T-cell responses to intracranial tumors as a single agent. The results must be interpreted with caution considering anatomical and biological differences between mice and humans. Nevertheless, Aldara that is being used as a vaccine adjuvant in clinical trials may have direct antitumor effects that are independent of exogenous antigen. Further studies in humans are warranted.
局部咪喹莫特乳膏（商品名：Aldara）是一种 Toll 样受体（TLR）7 激动剂，已被批准用于治疗皮肤肿瘤。Aldara 也被用作临床试验中胶质母细胞瘤和其他肿瘤患者的疫苗佐剂。Aldara 的主要作用机制是在应用部位附近局部激活 TLR7(+)细胞。在这里，我们报告了一个意外的发现，即 Aldara 作为单一药物在患有颅内肿瘤的小鼠中具有治疗和免疫调节活性。在皮肤表面重复给予 Aldara 可显著提高携带颅内 GL261 神经胶质瘤和 EMT6 乳腺癌的小鼠的存活率。Aldara 治疗与血液和脑肿瘤部位 CD4(+)Foxp3(+)调节性 T 细胞数量减少有关。用 Aldara 治疗的小鼠在血液中表现出普遍的淋巴细胞减少，同时脑肿瘤浸润的 CD4(+)和 CD8(+)T 细胞和树突状细胞增加。脑浸润的 CD8(+)T 细胞是肿瘤反应性的，如 GL261 依赖性脱颗粒和干扰素-γ分泌所证明的那样。此外，可溶性咪喹莫特以 TLR7 非依赖性方式直接抑制 GL261 细胞的增殖。这是第一个证明局部应用咪喹莫特可以增强 T 细胞对颅内肿瘤的反应作为单一药物的报告。鉴于小鼠和人类之间的解剖学和生物学差异，必须谨慎解释这些结果。然而，正在临床试验中用作疫苗佐剂的 Aldara 可能具有独立于外源性抗原的直接抗肿瘤作用。需要在人类中进行进一步的研究。
