淋巴
医学
免疫抑制
淋巴结
免疫疗法
CD8型
癌症研究
胶质瘤
免疫系统
离体
细胞毒性T细胞
免疫学
病理
体内
化学
生物
体外
生物技术
生物化学
作者
John Choi,Ayush Pant,Ravi Medikonda,Young-Hoon Kim,Denis Routkevitch,Laura Saleh,Luqing Tong,Hok Yee Chan,Jessie R. Nedrow,Christopher M. Jackson,Christina Jackson,Michael Lim
出处
期刊:OncoImmunology
[Informa]
日期:2021-01-01
卷期号:10 (1)
被引量:7
标识
DOI:10.1080/2162402x.2021.1940673
摘要
Despite the advent of immunotherapy as a promising therapeutic, glioblastoma (GBM) remains resistant to using checkpoint blockade due to its highly immunosuppressive tumor milieu. Moreover, current anti-PD-1 treatment requires multiple infusions with adverse systemic effects. Therefore, we used a PCL:PEG:PCL polymer gel loaded with anti-PD-1 and implanted at the site of lymph nodes in an attempt to maximize targeting of inactivated T cells as well as mitigate unnecessary systemic exposure.Mice orthotopically implanted with GL261 glioma cells were injected with hydrogels loaded with anti-PD-1 in one of the following locations: cervical lymph nodes, inguinal lymph nodes, and the tumor site. Mice treated systemically with anti-PD-1 were used as comparative controls. Kaplan-Meier curves were generated for all arms, with ex vivo flow cytometric staining for L/D, CD45, CD3, CD4, CD8, TNF-α and IFN-y and co-culture ELISpots were done for immune cell activation assays.Mice implanted with PCL:PEG:PCL hydrogels carrying anti-PD-1 at the site of their lymph nodes showed significantly improved survival outcomes compared to mice systemically treated with anti-PD-1 (P = .0185). Flow cytometric analysis of brain tissue and co-culture of lymph node T cells from mice implanted with gels demonstrated increased levels of IFN-y and TNF-α compared to mice treated with systemic anti-PD-1, indicating greater reversal of immunosuppression compared to systemic treatment.Our data demonstrate proof of principle for using localized therapy that targets lymph nodes for GBM. We propose an alternative treatment paradigm for developing new sustained local treatments with immunotherapy that are able to eliminate the need for multiple systemic infusions and their off-target effects.
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