Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences , University of Science and Technology of China , Hefei 230027 , P.R. China.
Guangzhou Regenerative Medicine and Health Guangdong Laboratory , Guangzhou 510005 , P.R. China.
Nano Lett. 2019 Aug 14;19(8):5356-5365. doi: 10.1021/acs.nanolett.9b01807. Epub 2019 Jul 12.
Certain chemotherapeutics (e.g., oxaliplatin, OXA) can evoke effective antitumor immunity responses by inducing immunogenic cell death (ICD). Unfortunately, tumors always develop multiple immunosuppressive mechanisms, such as the upregulation of immunosuppressive factors, to counteract the effects of immunogenic chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1), a tryptophan catabolic enzyme overexpressed in tumor-draining lymph nodes (TDLNs) and tumor tissues, plays a pivotal role in the generation of the immunosuppressive microenvironment. Reversing IDO1-mediated immunosuppression may strengthen the ICD-induced immune response. Herein, we developed a nanoenabled approach for IDO1 pathway interference, which is accomplished by delivering IDO1 siRNA to both TDLNs and tumor tissues with the help of cationic lipid-assisted nanoparticles (CLANs). We demonstrated that the contemporaneous administration of OXA and CLAN could achieve synergetic antitumor effects via promoting dendritic cell maturation, increasing tumor-infiltrating T lymphocytes and decreasing the number of regulatory T cells in a subcutaneous colorectal tumor model. We further proved that this therapeutic strategy is applicable for the treatment of orthotopic pancreatic tumors and offers a strong immunological memory effect, which can provide protection against tumor rechallenge.
某些化疗药物（如奥沙利铂，OXA）通过诱导免疫原性细胞死亡（ICD）可以引发有效的抗肿瘤免疫反应。不幸的是，肿瘤总是会发展出多种免疫抑制机制，如免疫抑制因子的上调，以抵消免疫原性化疗的作用。吲哚胺 2,3-双加氧酶-1（IDO1）是一种在肿瘤引流淋巴结（TDLNs）和肿瘤组织中过度表达的色氨酸分解酶，在产生免疫抑制微环境中发挥着关键作用。逆转 IDO1 介导的免疫抑制可能会增强 ICD 诱导的免疫反应。在此，我们开发了一种纳米增强的 IDO1 通路干扰方法，该方法通过阳离子脂质辅助纳米颗粒（CLANs）将 IDO1 siRNA 递送到 TDLNs 和肿瘤组织中来实现。我们证明，OXA 和 CLAN 的同时给药可以通过促进树突状细胞成熟、增加肿瘤浸润性 T 淋巴细胞和减少调节性 T 细胞的数量，在皮下结直肠肿瘤模型中实现协同抗肿瘤作用。我们进一步证明，这种治疗策略适用于治疗原位胰腺肿瘤，并提供强大的免疫记忆效应，可以提供对肿瘤再挑战的保护。
