Implantable Synthetic Immune Niche for Spatiotemporal Modulation of Tumor-Derived Immunosuppression and Systemic Antitumor Immunity: Postoperative Immunotherapy
Implantable Synthetic Immune Niche for Spatiotemporal Modulation of Tumor-Derived Immunosuppression and Systemic Antitumor Immunity: Postoperative Immunotherapy
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DOI：
10.1002/adma.201706719
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发表时间：
2018-05-03
影响因子：
29.4
通讯作者：
Lim, Yong Taik
中科院分区：
文献类型：
--
作者：
Phuengkham, Hathaichanok;Song, Chanyoung;Lim, Yong Taik
开发基于生物材料的免疫小生境，可以调节肿瘤微环境（TME）中的免疫抑制因子，将是改善当前癌症免疫治疗的关键技术。在这里，可植入的，工程化的3D多孔支架被设计成在骨髓源性抑制细胞（MDSC）消耗剂和癌症疫苗之间产生协同作用，骨髓源性抑制细胞（MDSC）消耗剂可以适应建立允许的免疫原性微环境以抵消肿瘤诱导的免疫抑制，癌症疫苗由全肿瘤裂解物和基于纳米凝胶的佐剂组成，其可以产生肿瘤抗原特异性T细胞应答。在晚期原发性4 T1乳腺肿瘤模型中，作为术后治疗的合成免疫生态位（称为immuneCare-DISC，iCD）的局部瘤周植入可产生全身抗肿瘤免疫，并防止手术部位的肿瘤复发以及残留肿瘤细胞迁移到肺部，从而实现100%的存活率。这些治疗结果是通过释放吉西他滨和募集/激活树突状细胞来抑制肿瘤和脾脏中的免疫抑制性MDSC、增强CD 4（+）和CD 8（+）T细胞群以及增加来自iCD的癌症疫苗的IFN-产生来实现的。这种通过iCD对肿瘤源性免疫抑制和疫苗诱导的免疫刺激的组合时空调节预计将为预防术后肿瘤复发和转移提供免疫生态位。
The development of biomaterial-based immune niches that can modulate immunosuppressive factors in tumor microenvironment (TME) will be a key technology for improving current cancer immunotherapy. Here, implantable, engineered 3D porous scaffolds are designed to generate synergistic action between myeloid-derived suppressor cell (MDSC)-depleting agents, which can accommodate the establishment of a permissive immunogenic microenvironment to counteract tumor-induced immunosuppression, and cancer vaccines consisting of whole tumor lysates and nanogel-based adjuvants, which can generate tumor antigen-specific T cell responses. The local peritumoral implantation of the synthetic immune niche (termed immuneCare-DISC, iCD) as a postsurgical treatment in an advanced-stage primary 4T1 breast tumor model generates systemic antitumor immunity and prevents tumor recurrence at the surgical site as well as the migration of residual tumor cells into the lungs, resulting in 100% survival. These therapeutic outcomes are achieved through the inhibition of immunosuppressive MDSCs in tumors and spleens by releasing gemcitabine and recruitment/activation of dendritic cells, enhanced population of CD4(+) and CD8(+) T cells, and increased IFN- production by cancer vaccines from the iCD. This combined spatiotemporal modulation of tumor-derived immunosuppression and vaccine-induced immune stimulation through the iCD is expected to provide an immune niche for prevention of postoperative tumor recurrence and metastasis.