Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Immunopharmacol Immunotoxicol. 2009 Jun;31(2):214-21. doi: 10.1080/08923970802380452.
The efficiency of cancer immunotherapy strategies is hampered by the existence of an intra-tumoral immunosuppressive environment involving tolerogenic dendritic cells (DCs) and regulatory T (T(reg)) cells. Hyperactivation of STAT3 in tumor is implicated in the generation of this immunosuppressive environment. The purpose of this study was to test whether simultaneous inhibition of STAT3 in tumor and TLR4 ligand-induced activation of DCs can modulate tumor-induced immunosuppression. For this purpose, the effects of a TLR4 ligand, 7-acyl lipid A, delivered by poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) to DCs on the activity of DCs and T(reg) cells was evaluated in vitro. In addition the immunomodulatory and anticancer effects of 7-acyl lipid A PLGA-NPs in combination with a STAT3 inhibitory agent, JSI-124, in a B16 mouse melanoma model was explored, in vivo. PLGA-NP delivery of 7-acyl lipid A to DCs reduced the suppressive effects of T(reg) cells on T cells in vitro. Besides, daily Intra-tumoral co-administration of 7-acyl lipid A PLGA-NPs and JSI-124 in C57BL/6 mice bearing B16-F10 tumor for 8 days resulted in a significant increase in the percentage of tumor infiltrated T cells as compared with control group that received PBS and monotherapy groups. The average tumor volume in the tumor-bearing mice that received JSI-124 plus 7-acyl lipid A PLGA-NPs combination therapy was found to be significantly lower than that in PBS and monotherapy groups. Our findings show a potential for the combination of STAT3 inhibition in tumor and TLR4 induced DC activation in increasing the efficacy of cancer immunotherapy.
癌症免疫疗法策略的效率受到肿瘤内免疫抑制环境的阻碍，该环境涉及耐受性树突状细胞（DC）和调节性 T（Treg）细胞。肿瘤中 STAT3 的过度激活与这种免疫抑制环境的产生有关。本研究的目的是测试同时抑制肿瘤中的 STAT3 和 TLR4 配体诱导的 DC 激活是否可以调节肿瘤诱导的免疫抑制。为此，评估了 TLR4 配体 7-酰基脂质 A 通过聚（乳酸-共-乙醇酸）纳米粒子（PLGA-NPs）递送至 DC 后对 DC 和 Treg 细胞活性的影响。此外，还研究了 7-酰基脂质 A PLGA-NPs 与 STAT3 抑制剂 JSI-124 联合在 B16 小鼠黑色素瘤模型中的免疫调节和抗癌作用。PLGA-NP 递送 7-酰基脂质 A 至 DC 可降低 Treg 细胞对 T 细胞的抑制作用。此外，在 C57BL/6 小鼠中，每天在肿瘤内共给予 7-酰基脂质 A PLGA-NPs 和 JSI-124 8 天，与接受 PBS 和单药治疗组相比，B16-F10 肿瘤小鼠的肿瘤浸润 T 细胞百分比显著增加。接受 JSI-124 加 7-酰基脂质 A PLGA-NPs 联合治疗的荷瘤小鼠的平均肿瘤体积明显低于 PBS 和单药治疗组。我们的研究结果表明，抑制肿瘤中的 STAT3 和 TLR4 诱导的 DC 激活相结合，可能提高癌症免疫疗法的疗效。
