Department of Nano Engineering, SKKU Advanced Institute of Nanotechnology (SAINT) and School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea.
Adv Mater. 2019 Oct;31(42):e1903242. doi: 10.1002/adma.201903242. Epub 2019 Sep 6.
Current cancer immunotherapy based on immune checkpoint blockade (ICB) still suffers from low response rate and systemic toxicity. To overcome the limitation, a novel therapeutic platform that can revert nonimmunogenic tumors into immunogenic phenotype is highly required. Herein, a designer scaffold loaded with both immune nanoconverters encapsulated with resiquimod (iNCVs (R848)) and doxorubicin, which provides the polarization of immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) into tumoricidal antigen-presenting cells (APCs), rather than depleting them, as well as in situ vaccination that can be generated in vivo without the need to previously analyze and sequence tumor antigens to favor neoantigen-specific T cell responses is suggested. Local and sustained release of iNCVs (R848) and doxorubicin from the designer scaffold not only reduces the frequency of immunosuppressive cells in tumors but also increases systemic antitumor immune response, while minimizing systemic toxicity. Reshaping the tumor microenivronment (TME) using the designer-scaffold-induced synergistic antitumor immunity with ICB effects and long-term central and effector memory T cell responses, results in the prevention of postsurgical tumor recurrence and metastasis. The spatiotemporal modulation of TMEs through designer scaffolds is expected to be a strategy to overcome the limitations and improve the therapeutic efficacy of current immunotherapies with minimized systemic toxicity.
目前基于免疫检查点阻断（ICB）的癌症免疫疗法仍然存在反应率低和全身毒性的问题。为了克服这一限制，非常需要一种能够将非免疫原性肿瘤转化为免疫原性表型的新型治疗平台。在此，提出了一种设计支架，该支架负载了封装有瑞喹莫德（iNCVs（R848））和阿霉素的免疫纳米转换器，能够将免疫抑制性肿瘤相关巨噬细胞（TAMs）和髓系来源抑制细胞（MDSCs）极化为杀瘤性抗原呈递细胞（APCs），而不是耗尽它们，以及原位疫苗接种，这种接种可以在体内产生，而无需事先分析和测序肿瘤抗原以促进新抗原特异性 T 细胞反应。从设计支架中局部和持续释放 iNCVs（R848）和阿霉素不仅可以减少肿瘤中免疫抑制细胞的频率，还可以增强全身抗肿瘤免疫反应，同时最大限度地减少全身毒性。使用设计支架诱导的协同抗肿瘤免疫与 ICB 效应和长期中枢和效应记忆 T 细胞反应重塑肿瘤微环境（TME），可预防术后肿瘤复发和转移。通过设计支架对 TME 的时空调节有望成为一种策略，以克服当前免疫疗法的局限性并提高治疗效果，同时最大限度地减少全身毒性。
